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\subsection {Summary of the Network}
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\begin{longtable}{|p{1.5cm}|p{1.5cm}|p{1.1cm}|p{5.5cm}|p{3cm}|p{5.5cm}|p{1cm}|p{1cm}|}
\caption{Temporal and Causal Explanations of the Current Network}
\hline
\textbf{Target} &
\textbf{Source} &
\textbf{Deduced Time} &
\textbf{Duration + Action} &
\textbf{Boolean function} &
\textbf{Biological function} &
\textbf{Time References} &
\textbf{Func. Reference} \\
\hline
\endfirsthead
\multicolumn{8}{c}%
{\tablename\ \thetable\ -- \textit{Continued ... Temporal and Causal Explanations...}} \\
\hline
\textbf{Target} &
\textbf{Source} &
\textbf{Deduced Time} &
\textbf{Duration + Action} &
\textbf{Boolean function} &
\textbf{Biological function} &
\textbf{Time References} &
\textbf{Func. Reference} \\
\hline
\endhead
\hline \multicolumn{8}{r}{\textit{Continued on next page}} \\
\endfoot
\hline
\endlastfoot
Receptor & Mitogen & 0-4,5 hours & nano seconds & Receptor=Mitogen & physical binding of receptor, stay activated till late G1 phase. Once cell become independent of extracellular signal, either the ligand or the reeptor are degraded and sequestered via endocytic vehisicle OR through arrestin process Or by PTP process. & \cite{kruger2008receptortime} & \cite{kruger2008receptortime} \\ \Xcline{1-8}{0.6pt}
Lipid & Receptor & 1-8 & From until endocytised & Lipid=Receptor & membrane dynamics help control cell cycle events and orgenll regulations. & \cite{hoffmann1999Lipidrhoshrinkmp3bmp4swelFUNC} & \cite{carlton2020membraneLipidFUNC} \\ \Xcline{1-8}{0.6pt}
PLC & Lipid/Rec. & 2 & 0-30(peak) ends 4 hour starts again in 5th hour and peaks at 11 hour. (Either in G1/S boundary or S start) & PLC=Lipid\&Receptor & Activity is dependant on receptor signal. One possible deactivation is the internal negative environment which repels the XY linkers in the PLC domain for autoinhibition. Involved in K, Ca+ TRPVs channel opening & \cite{lukinovic2007PLCtime,kadamur2013PLCinhibition}& \cite{rillema1989PLCFUNC} \\ \Xcline{1-8}{0.6pt}
\multirow{2}{=}{PIP2} & Lipid & \multirow{2}{=}{2} & Synthesis 3-8 min & \multirow{2}{=}{PIP2=Lipid\&!PLC} & \multirow{2}{=}{} & \cite{harraz2020pip2time} & \multirow{2}{=}{\cite{cao2019kPIP2toRASreal,shyng1998pip2toKatp,liang2019PIP2toRAS,zhang2019piptoRhoFun2,babich2015PIP2roleinNHEFUNCPIPFUnc}} \\ \cline{2-2} \cline{4-4}
& PLC & \ruleforfive & Hydrolysis for PIP3 half min. duration is 10-30 mins unstable half life, bit shorter than IP3. PLC cleaves PI into PIP2 and DAG & & & & \\ \Xcline{1-8}{0.6pt}
\pagebreak
\multirow{2}{=}{PKC} & Ca1 & 10 \ruleforfive & \multirow{2}={2 min onwards- Either basal or released Ca makes a complex for full activation. Sustained activation for Cl/Bicarb. Remains ON and responsible for MLC phosphorylation. } & \multirow{2}{=}{PKC=Ca1|to Ca8 \- \&PIP2} & \multirow{2}{=}{PKC also acts to activate RhoA by activating ROCK. Also, the activation of channels Therefore, its activity is required} & {\cite{xia1996PKCtime,nishizuka1992PKCtime2} & \multirow{2}{=}{\cite{gutierrez2019CalciumtoPKCtoMAPKrole,lipp2011PKCandCalicumroleFUNC,hardy1995pkctoclswell,zhang2007PKCtoAQ,foster2010PKCtoOsmolyte1,tchoumkeu1996PKCtoTaurine}} \\ \cline{2-3}
& PIP2 & 3 & & & & & \\ \Xcline{1-8}{0.6pt}
\multirow{2}{=}{IP3} & PLC & 2 & \multirow{2}{=}{A range of 3-15 for initiation 5 mins- Untill depolarmerizaiton} & \multirow{2}{=}{IP3= PKC|PLC\&PIP2} \ruleforfive & \multirow{2}{=}{PLC hydrolyse PIP2 to make IP3. IP3 acts synyergistically in presence of PKC. duration is 40 mins and depends on Calcium production} & \multirow{2}{=}{\cite{antony2007ip3time}} & \multirow{2}{=}{\cite{decuypere2011IP3FUNC}} \\ \cline{2-3}
& PIP2 & & & & & & \\ \Xcline{1-8}{0.6pt}
\multirow{3}{=}{IEG} & RAS & 5 & \multirow{3}{=}{Ras/Raf/MAPK pathway coincide with IEG 15 - 10 min. Duration is 2 hours} & \multirow{3}{=}{IEG=RAS\&MAPK \- \&Ca\&!MTORC1} & no direct interaction is found. However, it activates IEG through downstream signaling processes. & \multirow{2}{=}{\cite{kovacs2008iegtime,aitken2015iegtime2}} & \cite{murphy2004IEGFUNC} \\ \cline{2-3}
& Calcium & & & & MAPK trnaslocates into the nucleus which is why there's no signalling. This translocation causes transcription of IEG which stops after 2hrs & & \\ \cline{2-3}
& MAPK & 3 & & & & & \cite{chao1992MAPKFUNC2} \\ \Xcline{1-8}{0.6pt}
RAS & PIP2 & 5 & Post translational modification with the help of PIP2 makes ras to translocate to membrane 5 - 10 min. closed in 4th hour once mapk is transported to nucleaus & RAS=PIP2\&Receptor & PIP2 activates RAS when its cleaved into DAG. DAG activates RAS when only when its C1 responsive domain is active. Ras activation slows down and eventually stops during mid G1 when MAPK activity is highest \rulefortwo & {\cite{murakoshi2004RAStime,cao2019kPIP2toRASreal}} & {\cite{topham2001RASFUNC}} \\ \cline{2-3}
& Receptor& & & & & & \\ \Xcline{1-8}{0.6pt}
\pagebreak
\multirow{5}{=}{MP1} & PKC & 10 & \multirow{5}{=}{PIP2 and PKC conjunction with channels in bilayer membrane for phosphorylation ATP consumption throughout Shrinkage and depol causes kATP to block and respectively other members in MP1} & \multirow{5}{=}{MP1=PKC\&Lipids \- |PIP2\&!Ca6-8\&!Depol} & \multirow{5}{=}{Ion channels open a transient and quick opening, depending on the environment and signal received.} & & \multirow{5}{=}{\cite{shyng1998pip2toKatp,burger2000receptorFUNCbyCholesterol,gou2018protein,Wangsp,urrego201BLX4ZNU8hKPuTvEuBpDmukxx1otFamYf5kmGx9BPW8G1S}}\\ \cline{2-3}
& Lipid & 1 & & & & & \\ \cline{2-3}
& PIP2 & 1 & & & & & \\ \cline{2-3}
& Ca3 & 1 & & & & & \\ \cline{2-3}
& Depol. & 1 & & & & & \\ \Xcline{1-8}{0.6pt}
\multirow{4}{=}{MAPK} & RAS & 1 & \multirow{4}{=}{(5)-15 min. Full time} & \multirow{4}{=}{MPAK=RAS|Ca1 \- \&Receptor\&!AKT} & \multirow{4}{=}{Active at basal level throughout G1 phase. Around mid the signal is tranlocated to the Nucleas.} & \ \multirow{4}{=}{\cite{chen2012MAPKtime2,krueger2001MAPKtime3,kowtharapu2018MAPKtime}} & \ \multirow{4}{=}{\cite{chao1992MAPKFUNC2,white2010MAPKFUNC3,murphy2006MAPKFUNC,gutierrez2019CalciumtoPKCtoMAPKrole}} \\ \cline{2-3}
& Receptor & & & & & & \\ \cline{2-3}
& AKT & & & & & & \\ \cline{2-3}
& Ca1 & 1 & & & & & \\ \Xcline{1-8}{0.6pt}
\multirow{6}{=}{MP2} & PKC/PLC & 8 & \multirow{6}{=}{Calcium release in 10 mins causes the opening of TRPV and activaiton of Kca- Shuts down in 40 mins when shrinkage is completed and calcium has gone back to buffer state.} & \multirow{6}{=}{MP2=PIP2\&PKC|PLC \- \&Ca1,2,3,4} & \multirow{6}{=}{on channels open a transient and quick opening, depending on the environment and signal received. Most channels in MP2 are involved in bringing in the exogenous calcium inside for calcium establishment and help in maintaining the depolymerization.} & \multirow{6}{=}{\cite{lotteau2013TRPV1andcatime,dadsetan2008ca2+andERandSOCtime3,schapansky2009ca2+andERtime2}} & \multirow{6}{=}{\cite{li2020CalciumTRPVactivatesRhomediatedrepol,ouadid2004G1Smembranepotentialrange,smyth2007MP2MP3aDepolFunc,capiod2011MP2Funcbycalcium}} \\ \cline{2-3}
& PiP2 & & & & & & \\ \cline{2-3}
& Ca1 & 5 & & & & & \\ \cline{2-3}
& Ca2 & 1 & & & & & \\ \cline{2-3}
& Ca3 & 1 & & & & & \\ \cline{2-3}
& Ca4 & 1 & & & & & \\ \Xcline{1-8}{0.6pt}
mTorC2 & PIP2 & 3 & PI3K pathways phosphorylate 5 - 10 min. 4 to 5 hours closed by AKT & MTorC2=PIP2\&!AKT & it gets active in 2-3 steps after activation of PIP2 and is inhibited by Akt in its abundance. & \cite{dalle2012mtorc2time,briz2014mtorc2andakttime2} & \cite{jacinto2004mTorC2andRhoroleinshrinkage,} \\ \Xcline{1-8}{0.6pt}
\multirow{2}{=}{AKT} & mTorC2 & 3 & \multirow{2}{=}{phosphorylated in 5- duration is 2 hours. Close at mid} & \multirow{2}{=}{AKT=mTorC2\&IP3} \ruleforfive & \multirow{2}{=}{Phosphorylation leads to activation of Akt around 5th hour. PIP2 Hydrolysis leads to activation of PDK1 which activates AKT. The Adapter protein in mTorC2 complex phosphorylate AKT.} & \multirow{2}{=}{\cite{wu2006akttime3,aksamitiene2010akttime,kiyatkin2006aktime2,briz2014mtorc2andakttime2}} & \multirow{2}{=}{\cite{chen2018RhoFUNC}} \\ \cline{2-3}
& IP3 & 5 & & & & & \\ \Xcline{1-8}{0.6pt}
\multirow{9}{=}{ER} & Ca1 & 1 & \multirow{9}{=}{A feedback loop by IP3 and calcium for continouse calcium release. 10 - 40min (Until depol.)} & \multirow{9}{=}{ER=All Calicum \&IP3} & \multirow{9}{=}{Major role of ER is to help in calcium release and calium establishments and also in sequestration of calicum after depolymerization.} & \multirow{9}{=}{\cite{cheon2013ca2+andERtime,schapansky2009ca2+andERtime2,lotteau2013TRPV1andcatime}} & \ \multirow{9}{=}{\cite{decuypere2011IP3FUNC}} \\ \cline{2-3}
& Ca2 & 1 & & & & & \\ \cline{2-3}
& Ca3 & 1 & & & & & \\ \cline{2-3}
& Ca4 & 1 & & & & & \\ \cline{2-3}
& Ca5 & 1 & & & & & \\ \cline{2-3}
& Ca6 & 1 & & & & & \\ \cline{2-3}
& Ca7 & 1 & & & & & \\ \cline{2-3}
& Ca8 & 1 & & & & & \\ \cline{2-3}
& IP3 & 1 & & & & & \\ \Xcline{1-8}{0.6pt}
Ca1 & ER & 1 & \multirow{3}{=}{} & Ca1=ER & \multirow{2}{=}{} & \multirow{2}{=}{\cite{cheon2013ca2+andERtime}}& \multirow{3}{=}{\cite{decuypere2011IP3FUNC}} \\ \cline{1-3} \cline{5-5}
\multirow{2}{=}{Ca2} & ER & 1 & & \multirow{2}{=}{Ca2=ER\&MP2} & & \\ \cline{2-3}
& MP2 & 6 & & & & & \\ \cline{1-3} \Xcline{1-8}{0.6pt}
Ca3 & \multirow{6}{=}{ER\& \ MP2} & 1 & & \multirow{6}{=}{Ca3,4,5,6,7|8= \ ER\&MP2} & & \multirow{6}{=}{\cite{cheon2013ca2+andERtime,schapansky2009ca2+andERtime2}} & \multirow{6}{=}{\cite{capiod2011MP2Funcbycalcium,smyth2007MP2MP3aDepolFunc,hepler2016DepolbyCatoShrinkFUNC2}} \\ \cline{1-1} \cline{3-3}
Ca4 & & 1 & & & & & \\ \cline{1-1} \cline{3-3}
Ca5 & & 1 & & & & & \\ \cline{1-1} \cline{3-3}
Ca6 & & 0 & & & & & \\ \cline{1-1} \cline{3-3}
Ca7 & & 0 & & & & & \\ \cline{1-1} \cline{3-3}
Ca8 & & 0 & & & & & \\ \Xcline{1-8}{0.6pt}
\multirow{2}{=}{CaM} & Ca3-8 & 20 & \multirow{2}{=}{} & \multirow{2}{=}{CaM=Ca3-8\&!P27} \ruleforfive & \multirow{2}{=}{CaM has been shown to be essential for CDK4 activation and nuclear cyclin D1–CDK4 complex accumulation during the G1 phase. Also assist in complex nuclear localization.} & & \multirow{2}{=}{\cite{hanson2004ERandCaandCaMFUNC,whitaker1990ERandCaandCaMFUNC2}} \\ \cline{2-3}
& P27 & & & & & & \\ \Xcline{1-8}{0.6pt}
\pagebreak
\multirow{12}{=}{Depol.} & MP1 and 2 & 5 & \multirow{12}{=}{5 and 5TRPV Channels activated by SOCE cause increased influx of calcium in the mid of global calcium wave. Around 20-40 mins} & \multirow{10}{=}{Depol=Ca1-8|MP1| MP2\&PIP2 \- \&!Rho\&!MLC} & Katp majorly from the MP1 and Exogenous Calcium and TRPVs from MP2 & \multirow{12}{=}{\cite{hsu2006DepolTime,buelto20ATPDepolstop,bernstein2003ATPDepolstop2}} & \multirow{12}{=}{\cite{o1997depolfunc,qin2012DepoltoShrinkFUNC,vartiainen2002DepolFUNC2,smyth2007MP2MP3aDepolFunc}} \\ \cline{2-3} \cline{6-6}
& PIP2 & 2 & & & PIP2 regulate cofilin activity by sequestration & & \\ \cline{2-3} \cline{6-6}
& Ca1 & 1 & & & Calcium acts on cofilin and gelsolin proteins for destablising the cytoskeleton. Further, it directly helps in dissociation of polymers with phisical binding with the help of ATP. & & \\ \cline{2-3} \cline{6-6}
& Ca2 & 1 & & & \multirow{7}{=}{} & & \\ \cline{2-3}
& Ca3 & 1 & & & & & \\ \cline{2-3}
& Ca4 & 1 & & & & & \\ \cline{2-3}
& Ca5 & 1 & & & & & \\ \cline{2-3}
& Ca6 & 1 & & & & & \\ \cline{2-3}
& Ca7 & 1 & & & & & \\ \cline{2-3}
& Ca8 & 1 & & & & & \\ \cline{2-3} \cline{6-6}
& MLC & 1 & & \multirow{2}{=}{} & MLC phosphatase upon receing signal from rho gtpase causes stress in cytoskeleton which further is depolymerised via cofilin severing the polymers & & \multirow{5}{=}{\cite{uchida1992MP3aClandKCCtoTaurinerelease,galietta1997MP3aCltoTaurinMP3b,smyth2007MP2MP3aDepolFunc,vazquez2008roleMP3abyrhoFUNC,hoffmann1999Lipidrhoshrinkmp3bmp4swelFUNC}}\\ \cline{2-3} \cline{6-6}
& RhoA & 2 & & & Rho activation through & & \\ \Xcline{1-8}{0.6pt}
\multirow{5}{=}{MP3a} & RhoA & & \multirow{5}{=}{The calcium mediated Chloride and Na channels are activated RhoA and MLC help in the activation} & \multirow{5}{=}{MP3a=Ca3-8\&PKC|PIP2 \- \&Depol\&Rho\&MLC} & \multirow{3}{=}{Rho GTPase pathways are Needed for Chloride channel functional but not activaiton.} & & \multirow{5}{=}{\cite{uchida1992MP3aClandKCCtoTaurinerelease,galietta1997MP3aCltoTaurinMP3b,smyth2007MP2MP3aDepolFunc,vazquez2008roleMP3abyrhoFUNC,nilius1999RhotoVracClMP3a,carton2002rhotoClMP3a1}} \\ \cline{2-3}
& MLC & & & & & & \\ \cline{2-3}
& Depol. & & & & & & \\ \cline{2-3} \cline{6-6}
& Ca3-8 & 1 & & & Exogenouse calcium is needed for Chloride channel activation & & \\ \cline{2-3} \cline{6-6}
& PKC\&PIP2 & 31 & & & ref from latex & & \\ \Xcline{1-8}{0.6pt}
Shrinkage & mTorC2 & 1 & \multirow{5}{=}{Combination of factors 5 - 40min} & \multirow{5}{=}{Shrinkage=mTorC2\&Ca1 \- |Ca3-8\&MP3a\&MP3b \- \&Depol} & MtorC2 role in shrinkage is advised via depolymerization and MLC& \cite{lang1998ShrinkTime2,wang2002ShrinkTime3,lang2007Shrinkageuponsignalreception,rit1JRpfow927XUoPtmgataMC5m5aLewzNYUP} &\cite{qin2012DepoltoShrinkFUNC,rit1JRpfow927XUoPtmgataMC5m5aLewzNYUP,hoffmann1999Lipidrhoshrinkmp3bmp4swelFUNC,hepler2016DepolbyCatoShrinkFUNC2,rit1JRpfow927XUoPtmgataMC5m5aLewzNYUP}\\ \cline{2-3}
& Depol. & & & & & & \\ \cline{2-3} \cline{6-6}
& Ca all & 15 & & \rulefortwo & Exogenous and Cytosolic Calcium help in Chloride channel activation which ultimately leads to Osmolyte release after depolymerization. & & \\\cline{2-3} \cline{6-6}
& MP3a & 1 & & \ruleforfive & \multirow{2}{=}{Channel activation (MP3a \& MP3b) through MLC is is responsible for actin cytoskeletal rearrangments} & & \\ \cline{2-3}
& MP3b & 10 & & & & & \\ \Xcline{1-8}{0.6pt}
\multirow{2}{=}{MP3b} & MP3a & 10 & \multirow{2}{=}{Taurine eflux by KCC and CL mediation and with the help of Activated PKCca} & \multirow{2}{=}{MP3b=MP3a\&PKC \ |PIP2} & \multirow{2}{=}{Shrinkage and hyperppolarization induced KCC and Cl channel leads to release of Osmolyte and taurine.} & & \cite{galietta1997MP3aCltoTaurinMP3b,hoffmann1999Lipidrhoshrinkmp3bmp4swelFUNC,zhang2007PKCtoAQ,deng2012MlcFUNC,jacinto2004mTorC2andRhoroleinshrinkage,uchida1992MP3aClandKCCtoTaurinerelease} \\ \cline{2-3}
& PKC\&PIP2 & & & & & & \\ \Xcline{1-8}{0.6pt}
\multirow{3}{=}{MP4} & PIP2 & & \multirow{3}{=}{MLC activation around 40 mins activates the channels in MP4. MP4 is switched off because of hypotonic environment} & \multirow{3}{=}{MP4=MLC\&PKC \ \&PIP2\&!MP5} & When Depolimerization ends. It should turn ON till end to produce hypotonic environment to shutdown mp4 (because mp4 is deactivated by hypotonic environment) and during it’s activation when a.a are being influxed in cell along with volume and other ions. The mtorc1 senses a.a… only a.a channels in mp5 turn off and AQ channels remains open & & \cite{jessen1992MP4FUNC,ciano2003MLCtoNKCCMP4,shrode1995MLCtoNHEMP4} \\ \cline{2-3} \cline{6-6}
& MLC & 10 & & & Depolymerization is needed to activate NKCC in MP4 & & \\ \cline{2-3} \cline{6-6}
& PKC & & & & Ref from Latex & & \\ \Xcline{1-8}{0.6pt}
\multirow{4}{=}{Swelling} & MP4 & 5 & \multirow{4}{=}{Swelling starts on the basis of NHE and NKCC activated Osmo and Taurin influx and with the help of Cl/Bicarb. Closes with NHE and AQ, TauT shutdown} & \multirow{4}{=}{Swelling= MP4\&MP5 \ \&ClBicarb\&Repol.} & \multirow{2}{=}{It is suggested that with the osmolyte influx there is a net influx of water for cell swelling and migration purposes.} & & \cite{hoffmann1999Lipidrhoshrinkmp3bmp4swelFUNC,schwab2001MP5SwellingFUNC,cala1980MS8fsusNAxGm7pWV4VXD3mGzDf5ryEccW8aporin,lang2007clbicarbonateinrvi1,cacace2014clbicarbonateinrvi}\\ \cline{2-3}
& MP5 & 1 & & & & & \\ \cline{2-3}
& ClBicarb & 30 & & & & & \\ \cline{2-3} \cline{6-6}
& Repol & 240 & & & Repol and Bicarb Channel work in collaboration till the end, because its dependant on MP5 and MP4 and RhoA & & \\ \Xcline{1-8}{0.6pt}
\newpage
\pagebreak
\pagebreak
\multirow{2}{=}{E2F} & CycD1\&2 & 15 & \multirow{2}{=}{4th hour to 8} & \multirow{2}{=}{E2F=CycD1|CycD2 \- |CycE1|CycE2\&PrB}\ruleforfive & \multirow{2}{=}{Produced cyclin D along with basal help in partial phosphorylation of pRb. Cyclin E after helps in complete phosphorylation of the Prb.} & \cite{jia2009PrBandE2Ftime} & \cite{jia2009PrBandE2Ftime,ezhevsky1997CycEbyhypophsopho} \\ \cline{2-3}
& CycE1\&2 & 10 & & & & & \\ \Xcline{1-8}{0.6pt}
\multirow{3}{=}{RhoA} & mTorC2 & 25 & \multirow{3}{=}{Activated by mTorC2 and through TRPV influx 15-3hours} & \multirow{3}{=}{RhoA=mTorC2|CycD1 \- \&!P27} & RhoA is activated through phosphorylation mediated by mTORC2. Activated rhoA directly recruits chloride intracellular channels to the membrane. & \cite{mong2008Rhotime2,gulhati2011Rhotime1,mong2008Rhotime2} & \cite{chen2018RhoFUNC,croft2006RhoFUNC2,denicourt2004RhoFUNC,vazquez2008roleMP3abyrhoFUNC} \\ \cline{2-3} \cline{6-6}
& CycD1 & 2 & & & Rho signaling is both sufficient to induce cyclin D1 transcriptional activity, and is required for EGF to induce cyclin D1 promoter activity. Also Rho helps in the translocation of CycD complex into nucleas & & \\ \cline{2-3} \cline{6-6}
& P27 & 5 & & & P27 is reponsible to RhoA inhibition to cease the downregulation effects of RhoA on cell's cytoskeleton. & & \\ \Xcline{1-8}{0.6pt}
\multirow{3}{=}{MLC} & PKC & 35 & \multirow{3}{=}{Initially active in 10 minutes, probably to play a role in Shrinkage via contractility. Then in 20 minutes, it takes 30 mins to phosphorylate and activates via Rho and Cam-Remians active for 1-2 hours} & \multirow{3}{=}{MLC=PKC|CaM\& RhoA} & Increases the phosphorylation of MLC to activate it and it remains activated until Repol. is done & \cite{ip2007MLCtime2,wei2011MLCexptime,kikkawa2014MLCtime1}& \cite{nozu1999MlcRepolMP5FUNC2,deng2012MlcFUNC,ulke2010MlcFUNC2,chen2008mlctorepol,ciano2003MLCtoNKCCMP4,barandier2003MlcRepolMP5FUNC} \\ \cline{2-3} \cline{6-6}
& Ca/CaM & 3 & & & CaM binds and activates MLCK which phosphorylates MLC for its activation & & \\ \cline{2-3} \cline{6-6}
& RhoA & 30 & & & RhoA GTPase phosphorylates the MLCKs for cytoskeleton contraction which ultimately leads to deolymerization. & & \\ \Xcline{1-8}{0.6pt}
\pagebreak
\multirow{4}{=}{Repol.} & PIP2\&MP4 & 35 & \multirow{4}{=}{After MLC Goes parallel with swelling. Closed when swelling is stopped} & \multirow{4}{=}{Repol=PIP2|MLC \- \&MP4\&RhoA\&!Ca1-8} & \multirow{2}{=}{PIP2 interacts with cytoskeletal proteins and help in repolimerization} & \cite{zeidan2007actinrepoltime,gulhati2011Rhotime1} & \cite{yoon2010DeandRePOLFUNC2,nozu1999MlcRepolMP5FUNC2,barandier2003MlcRepolMP5FUNC} \\ \cline{2-3}
& Swelling & & & & & & \\ \cline{2-3} \cline{6-6}
& RhoA & & & & Through the activaiton of MLC and deactivaiton of Cofilin protein. It helps in repolymerization & & \\ \cline{2-3} \cline{6-6}
& MLC & 1 & & & increases the phosphorylation of MLC to activate it and it remains activated until repolimerization is done & & \\ \Xcline{1-8}{0.6pt}
\multirow{3}{=}{Clbicarb} & IP3 and PKC & & \multirow{3}{=}{Closed by feedbackloop from NHE} & \multirow{3}{=}{ClBicarb=MP4\&PKC \ |IP3} \ruleforfive & \multirow{3}{=}{IP3 and PKC are the regulator of Cl-/HCO3- channel when there is excessive protonation in the cell to normalise the pH of the cell. This exchange is countered via Chloride for hyperpolarization.} & & \cite{lang2007clbicarbonateinrvi1,lee2020BiCarbFUNC,cala1980MS8fsusNAxGm7pWV4VXD3mGzDf5ryEccW8aporin} \\ \cline{2-3}
& & & & & & & \\
& MP4 & 240 & & & & & \\ \Xcline{1-8}{0.6pt}
\multirow{2}{=}{CycD1} & CaM & 1 & \multirow{2}{=}{Basal. Full time} & \multirow{2}{=}{CycDComp=CaM\&P27} & \multirow{2}{=}{Basal Cyclin D presence is regulated via Calcium/calmadulin and P27 proteins for activity and stability.} & \cite{muise1998CycDBasaltime} & \cite{hydbring2016CycDbasalFUNC} \\ \cline{2-3}
& P27 & 1 & & & & & \\ \Xcline{1-8}{0.6pt}
\pagebreak
\multirow{4}{=}{CycD2} & CaM & 200 & \multirow{4}{=}{1 hour to 4 and then starts in the middle of S till M. From mid till end} & \multirow{4}{=}{CycDProd=CaM \& \ IEG |MAPK\&!P27} & \multirow{4}{=}{Once, the IEG is activated via MAPK pathway kinases the production starts and CycD/CDK4 complex is formed for further regulation of pRb.} & & \\ \cline{2-3}
& MAPK & & & & & & \\ \cline{2-3}
& IEG & 230 & & & & & \\ \cline{2-3}
& P27 & 1 & & & & & \\ \Xcline{1-8}{0.6pt}
\multirow{4}{=}{MP5} & PLC & 50 & \multirow{4}{=}{after 10 mins of mtorc1 ending} & \multirow{4}{=}{MP5=PLC\&MLC \ |ClBicarb\&!PKC} & Phospho lipid contects (PLA) play a role in the activation of Osmolyte channels via mechanosensitvity & \cite{mong2008Rhotime2,zeidan2007actinrepoltime}& \cite{han2006MP5FUNC,schwab2001MP5SwellingFUNC,barandier2003MlcRepolMP5FUNC} \\ \cline{2-3} \cline{6-6}
& MLC+PKC & 50 & & & MLC through Phosphorylation and lnks via cytoskeleton. While, PKC has integral role in the Taurine channel activation & & \\ \cline{2-3} \cline{6-6}
& Swelling & 210 & & \ruleforfive & \multirow{2}{=}{Swelling and Chloride Bi carbonate exchanger help in maintaining the charge balance of Osmolytic protein entrance. Also, with osmolyte influx there is a net influx of water for cell swelling and migration purposes.} & & \\ \cline{2-3}
& Clbicarb & 0 & & & & & \\ \Xcline{1-8}{0.6pt}
RHEB & AKT & 300 & Closed by feedback loop of TCS1/2 & Rheb=AKT & AKT acts at TCS2 to activate it which further releases the Rheb Protein. & \cite{sato2009Rhebandmtorc1time}& \cite{alessi2009mTorC1andAKTandRhebFUNC2} \\ \Xcline{1-8}{0.6pt}
\pagebreak
\multirow{3}{=}{mTorC1} & MAPK & 140 & \multirow{3}{=}{after enriching with a.a it takes almost 20 mins to one hours for activation of mtorc1} & \multirow{3}{=}{MtorC1=MAPK\&Rheb \ \&MP5} & Proteins of MAPK pathway downregulates mTORC1 activity by downregulating cytoplasmic amino acid content & \cite{bauchart2010mTorc1time,manifava2016mTorc1time2,sato2009Rhebandmtorc1time}& \cite{liu201BgivXvAHYsY82TaGkQ9znVrsm8Ka4SYic,alessi2009mTorC1andAKTandRhebFUNC2,carriere2008mTorC1FUNC} \\ \cline{2-3} \cline{6-6}
& Rheb & 20 & & & Rheb Activation helps mToRc1 in sensing the A.A sufficiency which then leads to the termination of the osmolytic intake along with water content. & & \\ \cline{2-3} \cline{6-6}
& MP5 & 200 & & & Through MP5 the osmolytic intake produce a causal effect on A.A sensing. & & \\ \Xcline{1-8}{0.6pt}
CycE1 & mTorC1\&!P27 & 1 & & CycE(Basal)=mTorC1 \ \&!P27 & Once, mTorC1 is activated to sense A.A. It further releases P27 from basal Cyclin E. This Free/Active CycE helps in complete phosphorylation of pRb. & \cite{janbandhu2010CycEbasaltime}& \cite{cuyas2014CycEbasalFUNC,cyce} \\ \Xcline{1-8}{0.6pt}
\multirow{2}{=}{CycE2} & P27 & 5 & 2 hours prior to S & \multirow{2}{=}{CycE2(Prod)=pRb\&E2F \ \&p27} & PIP2 interacts with cytoskeletal proteins and help in depolimerization & \cite{lukaszewicz2005CycEprodatime}& \cite{ezhevsky1997CycEbyhypophsopho} \\ \cline{2-4} \cline{6-6}
& E2F & 180 & & & the Active T.F (E2F) is responsible for Cyclin E production in bulk. & & \\ \Xcline{1-8}{0.6pt}
CycE3 & P27 & 460 & At S & CycE3(Bound)=!p27 & The Produced Cyclin bounds with p21 to stay nuetral unless it recives a signal. & \cite{lukaszewicz2005CycEprodatime}& \cite{ezhevsky1997CycEbyhypophsopho,moser2018CycEProdandTransfertoSFUNC} \\ \Xcline{1-8}{0.6pt}
\multirow{3}{=}{P27} & MAPK & 32 & \multirow{3}{=}{Start till end.} & \multirow{3}{=}{P27=MAPK\& \ CycD1,2\&!RhoA} & \multirow{2}{=}{MAPK pathways help the transcription of P27 and along with basal amounts this P27 helps in the sequestration of CycD into the nucleus.} & & \cite{moser2018CycEProdandTransfertoSFUNC,larrea2009rhoblockbyp27one,besson2004Rhoblockbyp27two} \\ \cline{2-3}
& CycD1 & 1 & & & & & \\ \cline{2-3} \cline{6-6}
& Rho & 420 & & & RhoA has a sugnificant role in P21 degradation along with ubiquitin ligase proteins to help activate the Cyclin E for G1/S transfer. & & \\
\hline
\endfoot
\end{longtable}
\end{landscape}
\end{document}
