CSB327 Lecture 12 Summary

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Cell and Systems Biology
Maurice Ringuette

Lecture 12 Syndecan-4 - A family of transmembrane proteoglycans - The major of cell surface heparin sulfates - Structure o Ectodomain (N-terminus)  HS-GAGs are low affinity co-receptors  HS-GAGs bind to FN to activate intracellular signalling events that stabilize FA  HS-GAGs bind to several growth factors to present them to their cognate receptors  HS-GAGs bind to and present FGF to their cognate FGFR on the same cell  CS-GAGs o Single-span TM domain o Short endodomain (C-terminus)  C1  Ser183  Associates with actin cytoskeleton  V  Lysine rich domain  PIP2 binding domain  PKCα binding domain  Syndesmos binding domain  C2  PDZ binding domain (e.g., syntenin) - PI3K generates PI docking sites o PI  PIP  PIP2  PLC breaks down PIP2 into diacylglycerol and IP3 o PI3K adds phosphate PIP  PIP2 o PI3K adds phosphate PIP2  PIP3 o PIP2 and PIP3 serve as docking sites for proteins with PH domains o Both forms of PIP2 serve as docking sites for proteins with PH domains o PTEN dephosphorylate PIP2 and PIP3  Cancer cells have mutated PTEN - Regulation of focal adhesion turnover by syndecan-4 o Syndecan-4 underexpression forms smaller FA and decrease cell motility o Syndecan-4 overexpression forms larger FA and decrease cell motility o Syndecan-4 maintains an intermediate state of adhesion to promote cell migration - Mechanism o Binding of FN to α5β1 integrin increase the level of PIP2  Binding of FN to α4β1 is syndecan independent o PIP2 binds to the V domain of syndecan-4 o PIP2 promotes the oligomerization of syndecan-4 o PIP2-syndecan-4 complex recruits and superactivates PKCα by autophosphorylation o Clustering of syndecan-4 and PKCα recruits syndesmos to the PM o Syndesmos interaction with paxillin stabilizes FA o Syndesmos and paxillin are phosphorylated PKCα o FN binding to integrin  increase PIP2  PIP2 binds to syndecan-4  syndecan-4 oligomerization  superactivates PKCα  recruits syndesmos to PM  syndesmos binds to paxillin  promotes FA stability - Turnover o HS-GAGs are co-receptors for bFGF-2 o HS-GAGs presents bGFG-2 to bFGFR-2 on the same cell o HS-GAGS activate bFGFR-2 signalling o bFGFR-2 signaling recruits and activates PKCδ to the PM o PKCδ phosphorylates Ser183 on syndecan-4 in C1 domain o p-Ser183 inhibits the affinity of syndecan-4 for PIP2 o p-Ser183 inhibits syndecan-4 oligomerization o p-Ser183 inhibits PKCα superactivation o p-Ser183 promotes FA turnover o bFGF-2  recruits PKCδ to PM  phosphorylates Ser183  inhibits syndecan-4 oligomerization  promotes focal adhesion turnover o bFGFR-2 signaling activates Ser/Thr phosphatase 1/2A o Ser/Thr phosphatase 1/2A dephosphorylates Ser183 on syndecan-4 o Ser183 promotes syndecan-4 oligomerization  promotes FA formation o bFGF-2  activates phosphatase 1/2A  dephosphorylates Ser183  promotes syndecan-4 oligomerization  promotes FA formation - Integrin-mediated FA formation is dependent on syndecan-4 o Cell binding domain of FN  Cells attach and spread  No FA formation o Cell binding domain of FN + Activating Ab against syndecan-4  FA formation  Activating Ab is substituting for the absence of the heparin binding domain of FN o Cell binding domain of FN + Heparin binding domain of FN  FA formation o Absence of syndecan-4  Cells attach an spread  No FA formation o Absence of PKCα  No FA formation Integrins - Heterodimeric transmembrane receptors composed of non-covalently associated α and β subunits (e.g., 24 distinct heterodimers) o β1 subfamily can associate with 12 α subunits  inactivation of the β1 chain results in early embryonic death o β2 subfamily can associate with I-CAMs o αv subfamily restricted to WBCs - No intrinsic enzymatic activity o Inte
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