Cell Biology

Src Kinases Flip the Switch

Science's STKE  02 Nov 2004:
Vol. 2004, Issue 257, pp. tw390
DOI: 10.1126/stke.2572004tw390

Growth factor receptors, such as the platelet-derived growth factor receptor (PDGFR), and integrins interact to provide context-dependent responses to growth factors. For example, the response of oligodendrocytes to physiological concentrations of PDGF is different depending on the integrin present, either αVβ3 or α6β1, and composition of the extracellular matrix. Colognato et al. extend these observations and show that members of the Src family of tyrosine kinases also contribute to specifying the response of cultured primary oligodendrocytes to PDGF. The cells were depleted of either Lyn or Fyn using siRNA. Lyn was required for enhanced proliferative response of the progenitor cells to PDGF in the presence of the αVβ3 ligand fibronectin, and Fyn was required for enhanced survival response of newly formed oligodendrocytes to PDGF or neuregulin in the presence of the α6β1 ligand laminin 2. Fyn was also required for laminin to promote a switch in the survival signaling pathways activated by neuregulin from a phosphoinositide 3-kinase (PI3K) survival signal to a mitogen-activated protein kinase (MAPK) signal. Differentiation of cells plated on laminin in response to growth factor withdrawal was also dependent on Fyn and was unaffected in Lyn-deficient cells. Coimmunoprecipitation experiments indicated that Fyn formed a complex with α6β1 integrin and Lyn coimmunoprecipitated with the PDGFR and αVβ3. Activation (based on phosphorylation of the catalytic tyrosine) of Lyn was stimulated in progenitor cells grown on fibronectin, whereas Fyn was activated in cells grown on any of the tested substrates. However, in differentiated oligodendrocytes grown on laminin 2, the abundance of Csk, a kinase that inhibits Src family kinases, was decreased and Fyn inhibitory phosphorylation was decreased. The authors propose a model in which, in proliferating progenitor cells, αVβ3 integrin activates Lyn, while Fyn is kept inactive by Csk phosphorylation, and then upon axon contact and engagement of the α6β1 integrin, inhibition of Fyn is alleviated, resulting in MAPK-dependent survival signaling and differentiation.

H. Colognato, S. Ramachandrappa, M. Olsen, C. ffrench-Constant, Integrins direct Src family kinases to regulate distinct phases of oligodendrocyte development. J. Cell Biol. 167, 365-375 (2004). [Abstract] [Full Text]