July07, 2022,UK

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Abstract Volume: 4 Issue: 2 ISSN:

Title Inhibition in Proper Ser, S6K and in PLCγ2 Synthesis are the Main for Causing Osteoarthritis, Diabetes, and C-Lymphocytic Leukemia Diseases


Corresponding Author: Ashraf Marzouk El Tantawi, Biomedical and Molecular Studies Canada Ontario Toronto, Goldwin Ave, Egypt Cairo Giza.


Copy Right: © 2022 Ashraf Marzouk El Tantawi, This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Received Date: January 24, 2022

Published Date: February 02, 2022

Abstract

Introduction: proper S6K /BTK and PLCγ2 synthesis (which regulated by Ser phosphorylation pathway) are main regulations for thromboxane-A "TXA2" synthesis, and necessary for B-cell maturations and T-cells modulations and functions.

The main reasons for causing   Osteoarthritis "OA"  and diabetes diseases  are the deficiency in Ser amino acids and decreasing  in Ser phosphorylation pathway which necessary for proper  S6K productions, where normally the Ser phosphorylation  pathway is the basis of Ser /Thr phosphorylation signalling and is necessary  for proper Akt, S6K1 synthesis and necessary for RORs and IFNs synthesis and also necessary for running proper BTK for PLCγ2 productions , where S6K is main regulator for ATPase and for proper PLCγ1 and for PLCγ2 synthesis which necessary for bone growth and for  modulating  immune efficiency.

Osteoarthritis "OA" is characterized by a sharp expression in Gamma-Phospholipase C-1 "PLCγ1", with decreasing "or inhibition" in PLCγ2 "PLC beta" productions (regulated by synthase) due to inhibition or mutation in S6K and then in BTK (that are missing Ser TCC, TCA, TCG).

The increasing in PLCγ1 with Deficiency in Ser amino acids will lead to deficiency in Ser phosphorylation signalling  and deficiency in the pyrimidine kinases (PST-thymine and PS T-Cytosine kinases) synthesis , that lead to decreasing in synthase activity which will reflect down regulations in BTK pathways and  inhibition in PLCγ2 productions which  will reflect diabetes ( production of  Androgen instead of estrogen ),  and can reflect Osteoarthritis"OA" prognosis which depend on the percentage of Deficiency or inhibition in basic amino acids and their basic necessary signaling pathways .

The proper S6K are so necessary for reactivating both PLCγ1&2 , where phospholipase Cγ2 (PLCγ2) which activated  from a variety of cell surface receptors such as SyK "S6K".

The B-cells which originally are promoted by the function and activities of both PLCγ1&2 , but the deficiency in Ser amino acids will reflect decreasing in Ser phosphorylation pathways and then decreasing in Estrogen synthesis, with increasing in Androgen synthesis which lead to decreasing in PLCs isoforms production (decreasing in PLCγ2 and PLC alpha) and lead to pathogenic diabetes problem .T2DM is strongly connected with OA diseases and are linked together by the deficiency in Ser amino acids and their phosphorylation  , and any early decreasing in Ser and in hydroponic acids synthesis  can lead to both and more disease.

Pathogenic type 2 diabetes associated with progressive beta-cell impairment due to the mutations in the production of S6K1 (deficiency in Ser"TCT, TCC, TCA"), and inhibition in the PLCγ2 which due to inhibition or decreasing in Synthase and lead to deficiency in BCR activities. 

The releasing of PS/T-Thymine Kinases and PS/T-Cytosine kinases chains (mTORC1) from the phosphorylation oxydative process on Ser amino acids will lead to mutated S6K and Akt productions and decreasing or mutations in ATPase and GTPase which lead to decreasing in OPA1 repair and lead to synthesis of androgyne instead of estrogen which are depending on availability of hydrophobic amino acids synthesis including Ser and Tyr amino acids.

The effect of synthetase enzymes on biological molecules is for creating active gamma-subunits "PLCγ1" that can be modified by synthase effect for Beta-subunit synthesis "PLCγ2" then will be modified by phospholipase effects for alpha subunits productions.

The  releasing of pyrimidine kinases "PS/T-Thymine -Kinase and PS/T-Cytosine -kinase chains (mTORC1)" from  the phosphorylations oxidations process on Ser amino acids is so necessary steps for  proper S6K productions  which necessary for both IFN-Gamma and for PLCγ1 productions which are necessary for regulating normal PLCγ2 synthesis upon "BTK activity" then PLCγ2 are necessary for regulating BCR functions which imp for regulating both IgM and IgD activities for B-cell maturations , for adjusting anti-inflammatory processes and for T-cells modulations, then PLCγ2 is so necessary for thromboxane-A synthesis, and for bone growth and immune modulations .

Note that gamma oxydations regulated by Cox and both ATPase and GTPase, but beta oxidations regulated by synthase activities which depend on pyrimidine synthesis and availability in its biological molecules , where Inhibition in pyrimidine kinases productions "PS/T-Thymine -Kinase and PS/T-Cytosine -kinase chains (mTORC1)" will lead to inhibition in beta subunits productions "which depends on synthase oxidative processes" that can be the reason of decreasing in the hyperpolarization and in electrical  activity that will lead to decreasing in the abolition of Ça+, that the decreasing in hydroponic acids Tyr, Ser,... Will decrease or inhibit the activity of tyrosine phosphorylation pathways.

Deficiency in conversion of glutarate to glutamate and decreasing in proline (hydroponic acids) biosynthesis and availability can affect on cartilage synthesis and bone growth due to decreasing in stimulating mitochondrial OPA1 oxidations.

It's imp to note that Tyrosine phosphatase PTPs are important regulator of chondrogenic patterning and are critical regulators of tyrosine phosphorylation that its activity depends on Tyr, Ser synthesis (hydrophobic acids) and on JAK state signaling activities.

And so, the proline-rich tyrosine kinases regulate proper PLCs isoforms which compete for binding site at the very C terminus of fibroblast growth factor for osteorogenitor embryonic   development, and bone growth. Synthetase is the main regulator for PLCγ1 functions followed by synthase effects for active beta-subunits “PLCγ2” productions which can be able to  "upregulate phospholipase abtivity" for alpha subunits (PLC-alpha) productions (alpha oxidations) for reactivating fibroblast growth factor receptor (FGFR2), for reactivating both IgM and IgD, and for TLR4 productions for osteoblast processes .

PLCγ1 can competes for a binding site at the very C terminus of FGFR2 for embryonic development and for bones growth, where, PLCs isoforms are involved in multiple stages in TLR4, in interferons synthesis , and in anti-inflammatory midulations .

PLCγ1 recruit to CSF-1 can follow imp stages for producing PLCγ2 which is necessary for activating  anti-inflammatory where, IFN-γ can be used activate both PLCγ1 and PLC-γ2 via an upstream of tyrosine kinase.

PLCγ1 recruited to CSF-1 for two pathways activities 1st / re-activating IFNs productions which regulate MHC class1 and class-two for modulating cell-surface antigen protein functions, 2nd / re-activating PLCγ2 for modulating T-cells activities, where PLCγ1 involved in the production of TRIM22 for mediating antiviral activities and anti-inflammatory processes through reactivating IFNs productions for PLCγ2 synthesis. PLCγ2 are so imp in anti-inflammatory processes (regulated by BTK functions) for thromboxane-A synthesis.

Inhibitions or mutations in S6K, in BTK and then in PLCγ2 productions will cause an inherent or inhibition in CXCL12 then followed by inherent or inhibition in CXCR4 then reflect inherent or inhibition in the regulation of B-cell growth through mutations in IgM and in IgD.

Proline amino acids are necessary for reactivate OPA1 anabolic oxidations started by activating synthetase for producing gamma-subunits “PLCγ1”, then modulated by synthase effect for beta "PLCγ2" synthesis, and then modulated by phospholipase alpha oxidations for   alpha-subunits "PLC-alpha" synthesis respectively for cartilage synthesis, for bone growth including antigen modulations (both IgM and IgD) and reactivation, and then for thromboxane-A synthesis.

Title Inhibition in Proper Ser, S6K and in PLCγ2 Synthesis are the Main for Causing Osteoarthritis, Diabetes, and C-Lymphocytic Leukemia Diseases

Introduction

Osteoarthritis is characterized by a sharp expression in Gamma-Phospholipase C-1 "PLCγ1", with decreasing in PLCγ2 "PLC beta" productions which can be improved by phospholipase oxidative processes for producing PLCγ2 and PLC-alpha which necessary for cellular proliferations, bone growth and calcium entry ", where PLCγ1 was highly expressed in human OA chondrocytes [1] which are implicated processes including mitogenesis and calcium entry.

Phospholipase C isoforms (PLCs) are essential mediators for cellular signaling and for cellular metabolism.

PLCs regulates multiple cellular processes including proliferations and biological bones growth by generating bioactive molecules such as inositol-1,4,5-triphosphate (IP3) and diacylglycerol.

That, PLCγ1 basis of inhibition-driven autophagy of IL-1β-treated chondrocyte confers cartilage protection against osteoarthritis. [2] PLCγ1 has the   roles of analyzing biological molecules “Osteoclast" through expressing its own functions, while PLCγ2 has the role of functioning PLCγ1 through running beta-oxidations (regulated by synthase) for both anti-inflammatory processes and for promoting proliferations through activating phospholipase alpha-oxidation for activating PLC-alpha for  proliferation and growth.

The slightly inhibition or decreasing in PLCγ1 will decrease osteoclast through decreasing analyzing process that will give priority for PLCγ2 synthesis “PLC-beta" regulated by synthase and its beta-oxidations for activating anti-inflammatory processes, and for promoting PLC-alpha production for proliferations   functions. The increasing in PLCγ2 synthesis regulated by BTK will activate osteoblast processes, bone growth, cellular proliferation, and T-cells modulations”. The availability of Proline amino acids is necessary for stimulating and accelerating OPA1 oxidative processes which will activate cartilages synthesis through PLCγ2 synthesis, where the availability of hydrophobic amino acids synthesis "eg: Tyr, Leu, Pro, Gly, Ser, ... etc" in vivo is important for creating gamma subunits synthesis upon synthetase effects.

Proline with necessary hydrophobic acids are necessary for and accelerating proper OPA1 oxidative processes which promote and activate necessary anabolic processes for cartilage synthesis through activating BTK pathways which regulate PLCγ2 synthesis for bone growth, and for modulating immune effectiveness.

The Deficiency in the conversion of glutarate to glutamate and decreasing in proline biosynthesis strongly affect on cartilage synthesis due to decreasing in the activation of mitochondrial OPA1 oxidative processes. [3]  Deficiency in the mitochondrial OPA1 membrane repairs process  can reflect deficiency in the proper S6K productions (which necessary for ATP and GTPase synthesis which necessary for  mitochondrial OPA1 repair, that  that will lead to decreasing in PLCs synthesis (decreasing in PLCγ2) then in SIRPα1, and in TLR4 biosynthesis, and  can reflect increasing in  catabolic analyzing processes (due to increasing in ATPase which depend on purines kinases production from Thr phosphorylation (PSTG-kinases and PSTA-kinases).

The  decreasing in PS /T Thymine kinases and in PS/T-Cytosine kinases (pyrimidine kinases ) productions due to decreasing in Ser and in hydrophobic acids synthesis including Tyr amino acids  will lead to androgen production instead of estrogen (diabetes disease) , where the synthetase activities in diabetic diseases can be increased till will analyze  phospholipids , foreign molecules and biological molecules (with decreasing or inhibition in pyrimidine kinases) lead to decreasing in the synthesis of anti-inflammatory tools eg PLCγ2 and IFN-beta productions . 

Proper S6K1 synthesis  promote ATPase and GTPase productions for OPA1 repair, for activating RORs pathways, for activating BTK pathways and for PLCγ2 productions, where all are depending on the purines and pyrimidine kinases productions through mTOR Ser/Thr phosphorylation pathways where necessary pyrimidine kinases are necessary for activating  BTK and then for PLCs productions, for IFN synthesis , for proper MHCs synthesis, and for proper bone growth with T-cells modulations .


Materials and Methods

Proper S6K /BTK are so necessary for regulating  PLCγ2 synthesis and are regulating proper thromboxane-A synthesis, B-cell maturations and T-cells modulations .

Where, it's so important to Understand the main reasons  that  cause  Osteoarthritis "OA" and diabetic diseases which are the deficiency of Ser amino acids and necessary hydroponic acids which lead to mutated S6K productions due to  deficiency or inhibitions in Ser phosphorylation  which normally is the basis of mTOR Ser /Thr phosphorylation Pathologies that are necessary for proper Akt, and S6K1 synthesis and then necessary for RORs and IFNs synthesis and also necessary  for proper PLCγ2 productions .

Proper S6K productions through availability of Ser and Tyr amino acids are  main regulator for ATPase synthesis and GTPase which necessary for OPA1 repair, and then for BTK pathways (which depends on Tyr a.a and on synthase effect for activating PLCγ2 ) and for  proper PLCγ1 synthesis which are regulating PLCγ2 synthesis too for necessary  bone growth and cartilage synthesis .

Osteoarthritis "OA" is characterized by a sharp expression in Gamma-Phospholipase C-1 "PLCγ1", with decreasing "or inhibition" in BTK which lead to decreasing or inhibition in PLCγ2 "PLC beta" production that will lead to decreasing in beta-cells maturation, decreasing in cellular proliferation, and decreasing in T-cells modulations.

The increasing in PLCγ1 with Deficiency in Ser and Tyr will lead to mutated S6K productions, and decreasing in proper synthase activity and decreasing in BTK processes that will lead to inhibition in PLCγ2 synthesis and will reflect deficiency in Estrogen synthesis and increasing Androgyne synthesis that will give the Symptoms of diabetes and   Osteoarthritis “OA" diseases.

We'll discuss why both diseases are connected and are caused due to deficiency in Ser and in hydroponic amino acids, that availability of the Tyr and other hydroponic acids and their phosphorylation is necessary for BTK activities, and hydroponic amino acids synthesis depends on JAK signaling regulated by synthetase enzymes.
 

Deficiency in proper S6K, in Ser and in Tyrosine  kinases  "which regulated firstly by synthetase" will lead to increasing in PLCγ1 with decreasing in PLCγ2 synthesis (which Regulated by availability  "pyrimidine kunases" ) will lead to Androgen synthesis instead of Estrogen which is Symptoms of   "diabetes" and Osteoarthritis"OA" diseases :

PLCγ1 is a protein molecules  that it's activity depending on Tyr phosphatase , and gamma common receptors synthesis  which regulated by JAK STAT signaling, and also regulated by synthetase enzyme where synthetase  is the main second enzyme  in OPA1 chains after COX enzyme (followed by synthase and phospholipase respectively ) and necessary for hydroponic acids synthesis  )  , that  synthetase enzymes is so necessary for creating signals transmission which can reactivate mTOR Ser/Thr signaling pathway and for  re-producing the active gamma-subunits which upon JAK signaling  will produce their active receptors necessary for activating gamma subunits "PLCγ1" for beta-subunits "PLCγ2" synthesis   upon synthase effect, then  will produce alpha subunits "PLC-alpha" upon phospholipase effects for activating   proliferations, and bones growth . 

The PLCγ1/PLCγ2 double-deficient B cell progenitors have reduced expression of genes related to B cell lineage, IL-7 signaling, and cell cycle. [4] That the activities of both PLCγ1&2 are linked to each other and are so necessary for re-activating  B-cells maturation , where,  PLCγ2  regulate the productions of both antigen-specific immunoglobulin necessary IgM and IgD synthesis necessary for anti-inflammatory processes, and necessary for T-cells modulations, therefore the deficiency or mutations in PLCγ2 will lead to decreasing in or lead to Malignant transformation in B cells that can cause mutations or inhibition in IgM and in IgD synthesis and will lead to inhibition or mutations in TXA2 synthesis too that can lead to a cancer problem as in  chronic lymphocytic leukemia (CLL) disease and can cause several other pathogenic problems as diabetes and OA diseases .

B-cells are firstly promoted by the productions of both PLCγ1 which upon BTK which regulate PLCγ2 synthesis , and depend on  proper S6K  synthesis "that deficiency in Ser amino acids will reflect decreasing in the productions of the two types of pyrimidine kinases (PSTT-K and PSTC-k) that will lead to mutations in S6K synthesis (decreasing in thymine nucleotides contents) and lead to decreasing  in Estrogen synthesis with increasing in Androgen synthesis which lead to pathogenic diabetes diseases .[5]

Proper S6K , Estrogen, and PLCγ2 synthesis are depending  firstly on availability of Ser amino acids and on the production of the two kinases (PSTTK and PSTCk) that are so necessary for reactivating the BTK pathways and reactivating the ribosomal ATPase which is necessary for  repairing the mitochondrial OPA1 membrain (through regulating  GTPase productions ), where proper OPA1  can be and BTK are necessary for  "PLCγ2" synthesis which regulated by synthase effect for B-cell receptor synthesis for B-cells maturations, and  then for anti-inflammation, then followed by creating PLC-alpha synthesis upon the upregulation of phospholipase functions for promoting proliferations and bone growth through SIRPa and TLR4 productions  .

In case of deficincy the mTOR Ser/Thr phosphorylations signalling due to deficiency in Ser phosphorylations and in Tyr kinases will lead to  mutated S6K, deficiency in BTK activities, and deficiency in synthase functions that will lead to deficiency in PLCγ2 synthesis and will lead to androgyne productions with deficiency in Estrogen synthesis which will give the symptoms of diabetes and Osteoporosis pathogenic diseases , and also the deficiency in PLCγ2 or will lead to  deficiency in TXA2 synthesis that can lead to cancer pathogenesis CLL diseases.

Pathogenic type 2 diabetes associated with progressive beta-cell  impairment due to deficiency in Ser and Tyr kinases synthesis that will lead to deficiency in BTK functions and inhibitions or decreasing in PLCγ2 productions  .

Tha availability of Ser, Tyr and necessary hydrophobic acids are necessary for re-activating BTK which necessary for promoting  PLCγ2 productions which is necessary for both B-cell maturation and for  thromboxane-A2 "TXA2" synthesis, and also for bone growth .[6A*]

The inhibition in active beta subunits productions “PLCγ2“can be the reason of decreasing in the hyperpolarization and then electrical activity will lead to decreasing in the abolition of Ça+ which will lead to decreasing in blood pressure and Ça precipitations in blood vessels.

Also, the deficiency in Tyrosine amino acids will prevent the production of tyrosine phosphatase which needed for the synthesis of phospholipase C 2 that promote cellular proliferation including TXA2 synthesis, and then the reduction and deficiency in Tyr amino acids "hydrophobic acids" will reduce or inhibit Drutons tyrosine kinases "DTK" followed by reduction in PLCγ2 synthesis.

Now it is important to consider that proper S6K and Tyr kinases are the main regulator for PLCγ2 synthesis, and it has been reported that the phospholipase Cγ2 (PLCγ2) is activated from a variety of cell surface receptors such as SyK "S6K", and BTK which phosphorylate and activate PLCγ2 [6].

Proper S6K1 synthesis is the basis for ATPase, and GTPase synthesis and also is the basis for ribosome repair where, GTPase is necessary for G-protein synthesis, for OPA1 membrane repair, and for ribosomal repairs that always necessary for regulating cellular growth and anti-inflammatory Processss.

As the GTPase is a regulator tool for BH4 and NO 3 productions for synthase repair and activity, As, S6K1 is the main regulator for both PLCγ1 synthesis and then for PLCγ2 synthesis upon synthase functions which later will regulate the beta-cells maturation and survival upon productions of firstly CXCL12 then CXCR4 productions.

Also, it has been approved that T2DM is connected with OA diseases , where T2DM has a pathogenic effect on OA through 2 major pathways involving oxidative stress and low-grade chronic inflammation resulting from chronic hyperglycemia and insulin resistance [7].

Pathogenic type 2 diabetes associated with progressive beta-cell impairment due to the not normal production of insulin which due to deficiency of Ser phosphorylation and other necessary amino acids (mainly Ser, Tyr, Leu, Pro a.a.) that will lead to decreasing "or mutation" in the S6K productions, and will lead to Androgen production instead of Estrogen, and the cholesterol which depend on pyrimidine synthesis is the main substrates for Estrogen synthesis regulated by ROR anabolic  pathways“, that will lead to high ATPase productions (due to availability of purines with decreasing in pyrimidine synthesis) with deficiency estrogen synthesis , that also can  activate  IFN gamma, but with decreasing in IFN-beta, and alpha that can lead to increasing in "catabolic processes " with decreasing in the ROR pathways "anabolic process", and decreasing in proper PLCγ2 productions that will reflect Ca+ precipitations and arterial hypertension.

Where, it has been reported that insulin activates the K-ATP channels of pancreatic β-cells and islets, resulting in membrane hyperpolarization, and the abolition of [Ca2+]i oscillations [8].

And, the low abolition of [Ca2+]i oscillations in the case of T2DM indicates decreasing or inhibition in pyrimidine synthesis “regulated by synthetase”, decreasing in synthase functions, and decreasing in PLCγ2 synthesis "that has the role of modulating inositol 1,4,5-trisphosphate-mediated calcium oscillations for bone growth " . Also, decreasing in membrane hyperpolarization can give reflection of decreasing in OPA1 synthase oxidations which reflect decreasing in membrane hyperpolarization and decreasing in PLCγ2 synthesis .

(PLCγ1) can be reactivated by platelet-derived growth factor "GF" receptors, insulin-like GF 1 receptor (which reflect deficiency in proper cells and bones growth), but in brief PLCγ1 productions can produced and re-functioned by several active growth factor (GF) receptors through feedback and by firstly reactivating synthetase followed by synthase then phospholipase which promote growth factor activities as epidermal GF receptor [EGFR], and platelet-derived GF receptor, where due to activating GFs processes it will be responsible for increasing hyperpolarization and functioning CA throughout the synthesis of PLCs that will responsible for running the pathway of bone growth and cellular biosynthesis processes.

The main PLCγ1 proper activities is regulated firstly by main ribosomes and by proper S6K productions from mTOR Ser /Thr phosphorylation pathways followed by JAK STAT signaling for producing the Tyr-phosphatase, gamma common receptors, and other necessary helical proteins receptors which adopt and activate PLCγ1&2 synthesis and activities for anti-inflammatory, for B-cells maturation, for T-cells modulation, and for bone growth and proper cellular proliferation.

PLCγ1 is a necessary Protein regulated firstly by chromosomes, then by ribosomes activities and by S6K which produced from mTOR Ser /Thr signaling pathway that regulated firstly by OPA1 synthetase and then activated by JAK STAT signaling for creating necessary receptors for both PLCγ1 and then PLCγ2 productions, where PLCγ2 is also regulated by BTK for proper PLCs isoforms productions for cellular proliferation and bones growth.

Hydrophobic acids such as Tyrosine, Ser, proline are necessary for facilitate the cellular and B-cells maturation and survival that protect proliferation processes of bones development (also can activate tumor growth in case of  synthase dysfunction when lose or deprived of some necessary amino acids) through facilitating OPA1 oxidative functions (that proline is necessary for  OPA1 enzymes activities which activate their function and bone cartilage growth ) ?and activate BTK pathways which necessary for FGFR2 gene expression for bones developments.

Where, Tyrosine amino acids increase alertness and bone development through activating tyrosine kinases, that Tyrosine phosphatases which are potential therapeutic targets for fighting bone disorders [9].

Protein tyrosine phosphatase (PTP) gamma (carry−ve charge regulated firstly by synthetase gamma-oxidations) has been proposed to be an important regulator of chondrogenic patterning, where PTPs are critical regulators of tyrosine phosphorylation at multiple stages of bone development and metabolism [10].

And, proline-rich tyrosine kinases regulate osteprogenitor cells and bone formations, [11] so Tyrosine and Proline (where their synthesis firstly regulated by synthetase in vivo) are regulated by PIPs and are critical regulators for multiple stages in bone development started by cartilage synthesis .

Tyrosine, Ser and proline are essential hydrophobic acids that produced in vivo upon the effects of synthetase enzymes on nutrients-mTOR , and on inflammations molecules for running pyrimidine synthesis  for creating and improving (modulating) active Gamma-subunits for PLCγ1 synthesis which modulated and regulate the beta subunits "PLCγ2" (upon BTK regulation) which necessary for increasing and modulating anti-inflammatory efficiency , then the PLCγ2 will be modulated for producing alpha "PLC-alpha" active subunits productions which necessary for proliferation, B-cells maturations, and bone growth .

Gamma-subunits firstly moderated by JAK STAT signaling for producing their own active gamma subunits receptors (as Gamma-common and other helical proteins) which can be promoted by IFN gamma too for  re-activating  PLCγ1,  PD-1, MHC-class-1 and class two, (where PLCγ2 promote antigens IgM and IgD), then MHC class two promote the SIRPα1,  TLR4, and PD-L1 productions necessary for  bone growth, cells developments and T-cells modulations . 

 

PLCγ1 competes for binding site at  very C terminus of FGFR2 for embryonic development and bones growth, where, PLC isoforms are involved in multiple stages in TLR4, and in interferons production:

PLCγ1 competes for a binding site at  C terminus of  fibroblast growth factor receptor (FGFR2) ( which plays an important role in bone growth, particularly during  "embryonic development" ) and  is sufficient to upregulate phospholipase activity [12]. That , S6K and synthetase  regulate PLCγ1 production  followed by BTK and synthase effects for beta-subunits ( "PLCγ2" ) productions which stimulate phospholipase "abtivity" for up regulating phospholipase activity for  active alpha subunits (PLC-alpha) productions which can reactivate the production of fibroblast growth factor and their receptors (FGFR2)  for full proliferations cycles, bone growth, cells maturation and T-cells modulations.

There are  strong relationships between PLCγ1&2 bio-activities and productions of the MHC class 1 and two  which promote SIRPα1, TLR4, and PDL1 productions which are necessary for proliferation,  cells  modulations and T-cells modulations .

Only Synthetase enzyme in OPA1 mitochondrial membrane are having the ability of hydrolysis biological molecules, inflammations  and phospholipid membranes in vivo ,but normally followed by the effects of synthase for moderate gamma subunits for producing PLCγ2 which will be moderated by phospholipase effects for PLC alpha production, but in deficiency in the synthase activities or in presence of mutated S6K  the Osteoclast will be activated  , where Osteoblast activity is characterized by proper availabilities of S6K, synthase activities, and PLCγ2 synthesis.

Some PLCs isoforms synthesis are involved in multiple stages in TLR4 and interferons  regulatory factors (IRFs) synthesis  [13].  Where it  means the involvement of only PLCγ2 in TLR4 synthesis and in promoting IFN-beta productions for modulate anti-inflammatory effectiveness, but PLCγ1 is promoting IFN gamma activities (PLCγ1 <¬¬> IFN gamma)   which responsible for promoting MHCs class-1 and class two then SIRPα1, TLR4 and PDL1 productions  for proliferation, bone growth and T_cells modulations . Also the availability of proper S6K1 for PLCγ1    are so necessary for activating IFN-beta and for TLR4.

So, proper PLCγ1 can be considered as important tools produced in vivo for activating IFN gamma and vice versa necessary for regulating PLCγ2 upon BTK activity for anti-inflammatory processes which will be upgraded and moderated by phospholipase activities for PLC alpha, SIRPα1 TLR4 and and for PD-L1 productions. 

Therefore, PLCγ1 regulate PLCγ2 production which regulated by tyrosine phosphatase receptors and by phospho-tyrosine receptors "PTyr-R" for activating PLCγ2 productions which then regulate PLC-alpha reproduction for bone growth, for B cells maturation, and for promoting anti-inflammatory steps.

Where, PLCγ2 are basically depend on JAK signaling for SH2B adaptor protein "which are a Tyr kinase receptor family" that necessary for BCR mediate B cells maturations [14"]  phospho-tyrosine "PTyr" are necessary for PLCs synthesis , and for SHP1Src homology region 2 domain?containing phosphatase 1   for regulating PLCs productions , for stimulate IFNs productions for anti-inflammatory processes and for  proliferations, B-cells maturation, and T-cells modulations . 

PLCγ1 is associated with numerous inflammatory diseases due to deficiency in synthase (which depend on availability of Ser and Tyr ) for PLCγ2 productions, that in  some diseases the mutation in S6K can be the main for causing those diseases (due to the deficiency in Ser phosphorylation signaling) and in other cases due to deficiency in proline and in Tyrosine hydroponic amino acids, that  healthy immune  is depending on the productions of PLCγ1 is for acting firstly on infections (by Gamma oxidation) which will promote  PLCγ2  productions upon the synthase and BTK activities for modulating  anti-inflammatory processes, and then will promote proliferations upon PLC alpha productions due to phospholipase regulations .

  
PLCγ1 recruit to Colony-stimulating factor-1 "CSF-1" is  followed by imp stages for producing PLCγ2 which is necessary for activating  anti-inflammatory cycles through activating IFNs which re-activate PLC-γ2 via upstream of tyrosine kinase :

The PLCγ1 has the specificity toward colony-stimulating factor receptor synthesis (CSF-1) signaling which expressed on the cell surface that can cause the cells to proliferate and differentiate into specific blood cells, and considered as a class III receptor tyrosine kinase that associated with Neuroinflammation, where PLCγ1 is recruited to the CSF-1 receptor following exposure to the cytokine. [15]  PLCγ1 specify for recruit to CSF-1 which necessary for promoting PLCγ2 synthesis for firstly re-activating anti-inflammatory steps then followed promoting proliferation steps through activating PLC alpha, SIRPα1,, TLR4 and then PD-L1 productions.  

CSF-1 is a members of the IL-1 receptor family regulated by Gamma oxidation by PLCγ1 for promoting PLCγ2 synthesis for re-stimulations IFN beta productions for modulating anti-inflammatory cycles and efficiency.

That, CSF1R-expressing cells may play an anti-inflammatory role or a cancer-suppressive role. [16] As PLCγ1 recruiting to CSF-1 for regulating PLCγ2 synthesis so CSF-1 play necessary role in promoting anti-inflammatory processes which regulated firstly by mitochondrial OPA1 enzymes, by proper S6K production, and by PLCγ1 synthesis.

Also, Tripartite motif (TRIM) 22 plays an important role in interferons (IFNs)-mediated antiviral activity and the Induction of TRIM22 by IFN-γ Involves JAK and PC-PLC/PKC. [17] So PLCs synthesis modulate and regulate Tripartite motif (TRIM) 22 too (which has antimicrobial activities) productions through activating IFNs production.

Also, IFN-γ activates PLC-γ2 via an upstream tyrosine kinase to induce activation of PKC-α. [18] that PLCγ2 regulated by PLCγ1 which can promote IFN-gamma production (through feedback) which has a variety of activities including PLCγ2 re-productions upon the necessity regulations of the upstream of tyrosine kinases for re-activating PKC-α.

PLCγ1 recruited to CSF-1 for two pathways activities 1st / re-activating IFNs productions which regulate MHC class1 and class two for modulating cell-surface protein activities, 2nd / activating PLCγ2 for modulating T-cells, where PLCγ1 involved in the production of TRIM22 for mediating antiviral activities and anti-inflammatory processes through reactivating IFNs productions for PLCγ2 synthesis which modulate T-cells and activate bone growth with activating necessary proliferation.  And also PLCγ1 promote IFN gamma which regulate MHC-class-I, MHC class-2 synthesis which promote, SIRPα1, TLR4, and PD-L1 synthesis.

Note that the inhibitions of PLCγ2 productions with PLCγ1 productions will lead to Osteoclast, but the proper balance of both PLCγ1 and PLCγ2 productions will lead to osteoblast where PLCγ2 are connected to IFNs productions too.

Also, the Colony-stimulating factor-1 "CSF-1" requires PI3-kinase-mediated metabolism for proliferation [19]

PLCγ1 recruited to Colony-stimulating Factor 1 "CSF-1" Depending on mTOR-Ser /Thr phosphorylation signaling for p13k and for proper S6K productions.

And, the inhibitions of of fatty acid synthase "FAS" activity by C75 is resulted in down regulation of phospho-AKT. [20]

The inhibition in synthase will reflect down regulations in OPA1 membrane and therefore Down regulation in p13k Akt and in S6K productions which necessary for ribosomes repair and for OPA1 repair upon GTPase re-synthsis.


PLCγ2 synthesis activate Osteoblast but PLCγ1 production with inhibition in PLCγ2 will activate Osteoclast (OC) by inhibiting the inositol 1,4,5-trisphosphate-

PLCγ1&2 synthesis are re-modulating variety of cellular pathways including osteoclast (OC) differentiation.

Where, PLCγ2 production is important to be in proper balance with PLCγ1 synthesis for running osteoblast and for inhibiting osteoclast, where the increasing in PLCγ1 productions with inhibition in PLCγ2 will activate osteoclast (OC) by inhibiting re-modulating inositol 1,4,5-trisphosphate "which mediated calcium oscillations and the up-regulation of the nuclear transcription factor NFATc1" . [21]

That, inositol 1,4,5-trisphosphate and diacylglycerol productions require phosphoinositide   synthase (PIS) for modulating OC differentiation through regulating transient receptor potential (TRP) channels which requires hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP) resulting in the generation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).

OPA1 synthase is necessary for creating sphosphoinositide   synthase (PIS) "regulated by proper S6K production which needed for GTPase synthesis which necessary for OPA1 membrane repairs".

Both PLCγ1 and sphosphoinositide   synthase (PIS) are imp for promoting PLCγ2 productions which necessary for upregulate phospholipase activity for PLC alpha for proliferations and bone growth, Where, increasing in PLCγ1 "with reduction or inhibitions in PLCγ2 productions will activate osteoclast but the reactivating proper PLCγ2 synthesis will activate Osteoblast.

PLCγ2, independent of PLCγ1, was required for receptor activator of NF-κB ligand–induced  osteoclastogenesis by differentially regulating nuclear factor of activated T cells c1 (NFATc1), [22] proper PLCγ2 Pathway for modulating osteoclastogenesis

Processes mediated by modulating T-cells to complete first the construction of anti-inflammations and the protection followed by the process of building bones growth and cells proliferation in the safety and protection of T-cells and macrophages. 

 

BTK regulate PLCγ2 synthesis which regulate both BCR and Thromboxane-A 2 synthesis, where, CLL disease due to full inhibition in PLCγ2:

Phospholipase Cγ2 is Critical for Dectin-1 mediated Ca2+ Flux and Cytokine Production in Dendritic Cells [23].

PLCγ2 has a critical activity in dendritic cells, where is having a Critical function for Development of a Murine Model of Inflammatory Arthritis. [24]

And , as PLCγ2 has a critical activity in dendritic cells for activating  NF-κB ligand–induced  osteoclastogenesis by differentially regulating nuclear factor-activated T cells c1 "NFATc1" As PLCγ2 production modulate first the capacity of T-cells of dendritic cells.

PLCγ2 is critical for B-cell receptor (BCR) for B cells maturation and functions, and PLCγ2 participates in TCR signal transduction and plays a role in T-cell selection [25]

It has been reported that Properdin and factor H production by human dendritic cells modulates their T?cell stimulatory. [26]

Properdin is plasma glycoprotein that when activated by PLCγ1 (and synthetase) that will be modulated by change unnecessary purines to pyrimidines for rebuilding necessary Tyr, Ser, Pro, then will be directed to x chromosome for translations and purification for being build by identical necessary sequences for being contain identical six thrombospondin that will be ready to be regulated and modulated by PLCγ2 for TXA2 synthesis and for modulating T-cells which mediate cellular and bone growth.

The increasing in PLCγ1 productions with deficiency or mutation in S6K and thus in Properdin will inhibit PLCγ2 functions and will reflect decreasing in B cells maturation with decreasing or mutations in the thrombospondin lead to inhibition in TXA2 synthesis and can lead to Autoinflammation and immune dysregulation (APLAID) which can cause rare monogenic autoinflammatory disease. 

That, the diverse pathologies associated with PLCγ2 are exemplified by distinct genetic variants, where inherited mutations at this locus cause PLCγ2-associated antibody deficiency and immune dysregulation. [27]

Thrombine activation is highly reactivate intermediate the true fibrin monomer and it rapidly, and irreversibly. [28]

That Thrombine is activated by PLCγ2 which intermediate fibrin monomer. Where, PLCγ2 involved with fibrin formation, where Bruton tyrosine kinase (Btk) activates PLCγ2,11,12 leading to thromboxane A2 (TXA2) synthesis.  [29]

So, proper PLCγ2 synthesis depend on PLCγ1 and on BTK activities that are necessary for regulating thromboxane-A 2 and fibrin and for re-modulating immune and T cells activities. Also, the antiplatelet and anti-thrombotic effects of Fc are carried out through oppression of PLCγ2 and subsequent DAG-PKC-TXA2 and IP3-[Ca2+]. [30]

The activation of PLCβ through Gq, which results in the formation of IP3 and diacyl glycerol, plays an important role in mediating αIIbβ3 activation. [31]

So in brief the proper S6K, PLCγ1, and BTK necessary for PLCγ2 productions which is necessary for B-cell maturation and T-cells modulations, and necessary for regulating thromboxane-A synthesis.


Chronic lymphocytic leukemia [CLL] reflect Inhibition in BTK and in PLCγ2 synthesis which  reflect Inhibition or impaire in Thromboxane-A :

Proline amino acids are required for Collagen synthesis [32] where, Collagen binds to its receptors and  activate  both the PLCγ2-DAG-PKC and PI3 kinase/Akt-p38 MAPK cascades, where p38 MAPK can activate cPLA2, which catalyzes arachidonic acid (AA) release to produce thromboxane A2 (TxA 2 ) formation [33]

Bruton's tyrosine kinase "BTK" activates PLCγ 2 variants mediating ibrutinib resistance in human CLL. [34]

BTK inhibitors [ibrutinib , CNX?774 ] significantly attenuated TPA?induced cell invasion and migration in MCF?7 cells and inhibit the activation of the phospholipase Cγ2/PKCβ signaling pathways [35]

BTK was initially shown to be defective in the primary immuno-deficiency X-linked a gamma-globulinemia (XLA) and is essential both for B cell development and function of mature. [36]

So, both of Collagen synthesis and BTK are the main functions for re-activating PLCγ2 which catalyzes arachidonic acid (AA) release to produce thromboxane-A2 (TXA 2 ) formation ( note the inhibition or mutation in BTK and PLCγ2 will inhibit TXA2 synthesis and will  cause Chronic lymphocytic leukemia), where both BTK and PLCγ2 are so necessary for B cells maturation and are critical for B-cell receptor (BCR), where, inhibition or reduction in BTK and in PLCγ2 will reflect Inhibition in B-cells maturation, inhibition in T-cells modulations, and inhibitions in TXA2 synthesis and will be the result of Chronic lymphocytic leukemia "CLL" disease. 

Vascular endothelial growth factor receptor (VEGFR) but not KIT, platelet-derived growth factor receptor (PDGFR) and FMS-like tyrosine kinase 3 (FLT3) are critical for CLL cell viability.[37]

MTOR Ser Thr phosphorylation pathway regulate S6K production and promote VEGF activities for reproducing TXA2 (but through PLCγ2 regulations) in one pathway, and the other pathway is stimulating the PLCγ1 pruductions and promoting BTK activities for activating PLCγ2 productions which will reactivate the proper TXA2 synthesis and mediate the activities of VEGF for producing TXA2, for reactivating tropomycine, and reactivating G-actin filaments activities.

My note is, the synthesis of proper TXA2 in vivo are fully depending on PLCγ2 and consequently on S6K and BTK activities and functions, but only VEGF are not enough and not satisfied for TXA2 synthesis. the proper S6K synthesis which will reactivate the PLCγ1 and DTK which will promote the PLCγ2 synthesis which I can consider it as the main necessary proper tools for TXA2 synthesis for blood synthesis, for bones maturations and for cells growth  and then  CLL cell viability.

So, PLCγ2 (which basically regulated by ribosomes, by S6K, and by PLCγ1) promote TXA2 synthesis which can stimulate and reactivate VEGF synthesis upon feedback for tropomycine and for G-actin filaments reactivations for running full cellular Biosynthesis, for blood filtering in veins, and for cellular metabolism.

Chronic lymphocytic leukaemia (CLL) is a malignancy of CD5+ B cells that is characterized by the accumulation of small, mature-appearing lymphocytes in the blood, in bone marrow and in lymphoid tissues due to PLCγ2 inhibition may due to full mutated S6K production .

PLCγ2 synthesis occurred mainly in bone marrow where normal  blood synthesis is regulated by skeletal tissue that is having orders from basic ribosomes ,but mature CLL blood are activated and formed only by the activities of mTOR Ser/ Thr signaling which promote the VEGF, toropomycine synthesis (where both cannot promote TXA2 synthesis without PLCγ2 availability ) that both VEGF and toropomycine are necessary for reactivate G-actin filaments and re purify blood in veins .

So why VEGF +toropomycine is producing white mature cells?? VEGF cannot regulate directly the PLCγ2 synthesis and consequently can't regulate TXA2 synthesis but   TXA2 synthesis cannot be done without PLCγ2 regulations.

Where VEGF responsible for increasing the plasma long lived-plasma cells (LLPC), then the generation of antigen-specific antibody for Durable humoral immunity (which produced by non-proliferating bone marrow. [38]

Old blood cells when passes through spleen will be broken to save iron which bind to PLCγ2 for regenerate new blood cells by PLCγ2 which extracted in spleen which are responsible for metals transportations and proliferation for new cells, but inhibition in PLCγ2 with increasing in the mutated S6K will inhibit TXA2 synthesis and will increase long lived plasma which increased by increasing in nutrients-mTOR signalling.

The B cell receptor (BCR) signaling pathway (which regulated by PLCγ2 synthesis and activities) has critical cell survival implications in B-cells malignancies, such as chronic lymphocytic leukemia (CLL).  small molecule tyrosine kinase inhibitors of members of the BCR signaling pathway have proven to be transformational in treatment of CLL. [39]

The B-cell receptor (BCR) is a key survival molecule for normal B cells and for most B-cell malignancies.

In CLL, engagement of the BCR (which regulated by PLCγ2) by antigen occurs in vivo, leading to down-regulated expression and to an unanticipated modulation of glycosylation of surface IgM,.[40]

So, inhibition in PLCγ2 synthesis will inhibit BCR signalling function that will lead to inhibition in modulation in IgM which normally done by BCR function for activating B-cells maturation.

The anti-apoptotic cell IgM natural antibodies can regulate inflammatory responses through ancient pathways of the innate immune system that first arose long before the initial emergence of the adaptive immune system. [41]

My note, PLCγ2 first regulate BCR activities which regulate both of IgM & IgD synthesis through synthase enzyme regulations, where IgM is more activé and less stable than IgD, that IgM necessary for modulating and regulating inflammatory immune response and anti-inflammatory processes through modulating T-cells reactivities.

 

Results and Conclusion:

Chronic lymphocytic leukemia [CLL] due to Inhibition in PLCγ2 synthesis " due to inhibition in OPA1 synthase" lead to inhibition in CXCR12 where CXCR12 is the main activator and regulator for CXCR4 synthesis Upton phospholipase effects on CXCR12.

Also inhibition in PLCγ2 Bio-Synthesis will reflect Inhibition in thromboxane-A2 production that TXA2 mainly regulated by PLCγ2 but not regulated by VEGF, where VEGF regulate white mature cells, and regulate Tropomycine activity.

Osteoarthritis "OA" is characterized by a sharp expression in Gamma-Phospholipase C-1 "PLCγ1" (which catabolize inflammations) , with decreasing "or  inhibition" in PLCγ2 "PLC beta" productions (which necessary for immune modulation, for B-cell maturation and for T-cells modulation and regulate TXA2 synthesis ) .

The increasing in PLCγ1 with Deficiency in Ser amino acids, and deficiency in proper S6K, with decreasing or inhibition in OPA1-synthase activity will lead to inhibition in PLCγ2 which lead to diabetes and early Osteoarthritis"OA" prognosis.

PLCγ2 are so necessary for re-modulating T-cells and immune efficiencies, and necessary for regulating antigen and thromboxane-A synthesis.

The inhibitions or reduction or mutations in BTK and in its main proper PLCγ2 producions will cause an inherent inhibition or reduction in CXCL12 then will be followed by inhibition or reduction in CXCR4 then will lead to inhibition in the regulation of B-cell maturation, migration, adhesion, and also lead to severe decreasiing in anti-inflammatory processes of immune productive efficiency.

Also, inhibition in BTK and PLCγ2 mainly will reflect Inhibition in the two antigens IgM in and IgD synthesis.

Chronic lymphocytic leukemia "CLL" reflect decreasing or inhibition on growth-promoting signaling via the B-cell receptor. The Bruton tyrosine kinase (BTK) is the important for PLCγ2 systems which is necessary for B-cell activities  and T-cells modulation.

Bruton tyrosine kinase (Btk) necessary to activates PLCγ2 ,11,12 which necessary to activate thromboxane A2 and necessary for modulating immune activities and T-cells too.

Both Collagen and BTK pathways are necessary tools for re-activating PLCγ2 which catalyzes arachidonic acid (AA) release to produce thromboxane-A2 (TXA 2 ) synthesis , and necessary for B cells maturation  and critical for B-cell receptor (BCR), where, inhibition in BTK and in PLCγ2 will reflect diabetes, Osteoarthritis, and the Chronic lymphocytic leukemia "CLL" disease depending on the percentage of Ser & hydroponic amino acids shortage and depending on the percentage of inhibition of necessary pathways needed for PLCγ2 synthesis and reactivities .

Also, inhibition in the availability of Ser, Tyr, Leu , Pro with inhibition in necessary hydrophobic amino acids synthesis and in BTK and then in PLCγ2 can lead to Osteosarcoma which is a cancer cases that produces immature bone  (due to mutins in PLCγ2 and in TLR4 productions ) found at the end of long bones, often around the knee .

Deficiency in proline with inhibition in Ser, Tyr,  leu (or mutations in synthase) and  in specific  beta-subunits-calcium carriar can reflect  mutations in the  PLCγ2 (beta subunits) productions due to deficiency in proper beta-oxidation that can lead to deficiency or inhibition  in the PLCγ2 and PLC alpha , and  in MHC class two, that will lead to deficiency or inhibition "or mutations" in  "SIRPα1 and in TLR4, PD-L1 then in PD-L1" lead to isolations to that area (due to precipitation of the un functioned calcium by PLCs) that can lead to mutated immature  bone and tissue synthesis .

 

References

1. Disruption of Phosphoinositide-Specific Phospholipases Cγ1 Contributes to Extracellular Matrix Synthesis of Human Osteoarthritis Chondrocytes August 2014 International Journal of Molecular Sciences 15(8):13236-46 DOI:10.3390/ijms150813236 PubMed.

2. PLCγ1 inhibition-driven autophagy of IL-1β-treated chondrocyte confers cartilage protection against osteoarthritis, involving AMPK, Erk and Akt Xiaolei Chen,Yue Wang,Ning Qu,Bing Zhang,Chun Xia  First published: 28 December 2020 https://doi.org/10.1111/jcmm.16245

Figure 1