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Integrins direct Src family kinases to regulate distinct phases of oligodendrocyte development.

Colognato H, Ramachandrappa S, Olsen IM, ffrench-Constant C - J. Cell Biol. (2004)

Bottom Line: Specific integrins expressed on oligodendrocytes, the myelin-forming cells of the central nervous system, promote either differentiation and survival or proliferation by amplification of growth factor signaling.Fyn associates with alpha6beta1 and is required to amplify platelet-derived growth factor survival signaling, to promote myelin membrane formation, and to switch neuregulin signaling from a phosphatidylinositol 3-kinase to a mitogen-activated protein kinase pathway (thereby changing the response from proliferation to differentiation).However, earlier in the lineage Lyn, not Fyn, is required to drive alphaVbeta3-dependent progenitor proliferation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Cambridge, Cambridge CB21QP, England, UK. colognato@pharm.sunysb.edu

ABSTRACT
Specific integrins expressed on oligodendrocytes, the myelin-forming cells of the central nervous system, promote either differentiation and survival or proliferation by amplification of growth factor signaling. Here, we report that the Src family kinases (SFKs) Fyn and Lyn regulate each of these distinct integrin-driven behaviors. Fyn associates with alpha6beta1 and is required to amplify platelet-derived growth factor survival signaling, to promote myelin membrane formation, and to switch neuregulin signaling from a phosphatidylinositol 3-kinase to a mitogen-activated protein kinase pathway (thereby changing the response from proliferation to differentiation). However, earlier in the lineage Lyn, not Fyn, is required to drive alphaVbeta3-dependent progenitor proliferation. The two SFKs respond to integrin ligation by different mechanisms: Lyn, by increased autophosphorylation of a catalytic tyrosine; and Fyn, by reduced Csk phosphorylation of the inhibitory COOH-terminal tyrosine. These findings illustrate how different SFKs can act as effectors for specific cell responses during development within a single cell lineage, and, furthermore, provide a molecular mechanism to explain similar region-specific hypomyelination in laminin- and Fyn-deficient mice.

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Model for integrin regulation of SFK activity during oligodendrocyte lineage progression. In oligodendrocyte progenitors, Lyn is associated with the PDGFαR–αVβ3 integrin complex and contributes to proliferation signaling. Catalytic Y397 of Lyn (orange) is phosphorylated after αVβ3 integrin ligation. Fyn is maintained in the inactive state by Csk phosphorylation of Fyn-inhibitory COOH-terminal Y531 (yellow). After axonal contact and ligation by α6β1 of the α2 chain laminins expressed in myelinating axon tracts, Lyn dissociates from the integrin–growth factor complex and Csk is downregulated, reducing Fyn phosphorylation at Y531 and promoting Fyn activity. Active Fyn–α6β1 complexes can then trigger PI3K and MAPK signaling, depending on the ligand binding of PDGFαR and ErbB2/4 receptors, respectively, thereby promoting oligodendrocyte survival, differentiation, and myelin formation.
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fig9: Model for integrin regulation of SFK activity during oligodendrocyte lineage progression. In oligodendrocyte progenitors, Lyn is associated with the PDGFαR–αVβ3 integrin complex and contributes to proliferation signaling. Catalytic Y397 of Lyn (orange) is phosphorylated after αVβ3 integrin ligation. Fyn is maintained in the inactive state by Csk phosphorylation of Fyn-inhibitory COOH-terminal Y531 (yellow). After axonal contact and ligation by α6β1 of the α2 chain laminins expressed in myelinating axon tracts, Lyn dissociates from the integrin–growth factor complex and Csk is downregulated, reducing Fyn phosphorylation at Y531 and promoting Fyn activity. Active Fyn–α6β1 complexes can then trigger PI3K and MAPK signaling, depending on the ligand binding of PDGFαR and ErbB2/4 receptors, respectively, thereby promoting oligodendrocyte survival, differentiation, and myelin formation.

Mentions: Myelinating oligodendrocytes provide a model system for understanding how ECM and growth factors regulate distinct aspects of cell behavior during development. We have shown previously that changing interactions between integrins and growth factor receptors within the membrane provide a mechanism for temporal and spatial specificity of growth factor signaling. Here, we identify the SFKs Fyn and Lyn as key effector molecules within these integrin–growth factor receptor complexes that selectively promote either proliferation or differentiation/survival. As such, they serve both to integrate the extracellular signals provided by ECM and growth factors and to translate these signals into specific cell behaviors during development. The illustration in Fig. 9 summarizes how these different integrins regulate distinct phases of the oligodendrocyte lineage by using distinct SFK partners and thereby ensuring correct timing and location for oligodendrocyte proliferation, survival, and, ultimately, myelin formation. In this model, the key association necessary for the specificity of each SFK is with the integrin, rather than with the growth factor receptor. In support of this, a role for SFKs in integrin signaling is well established, whereas a link between SFK signaling and PDGFαR signaling remains less clear. Triple gene knockouts revealed that Src, Yes, and Fyn were dispensable for PDGF-mediated signaling in fibroblasts, but necessary for several ECM-mediated functions (Klinghoffer et al., 1999). And, although PDGF deficiency leads to hypomyelination during development, this defect occurs in regions of the central nervous system that are unaffected in Fyn −/− mice (Fruttiger et al., 1999). Together, these findings are consistent with a model in which growth factor stimulation in the absence of integrin ligation is not sufficient to activate a requirement for SFK.


Integrins direct Src family kinases to regulate distinct phases of oligodendrocyte development.

Colognato H, Ramachandrappa S, Olsen IM, ffrench-Constant C - J. Cell Biol. (2004)

Model for integrin regulation of SFK activity during oligodendrocyte lineage progression. In oligodendrocyte progenitors, Lyn is associated with the PDGFαR–αVβ3 integrin complex and contributes to proliferation signaling. Catalytic Y397 of Lyn (orange) is phosphorylated after αVβ3 integrin ligation. Fyn is maintained in the inactive state by Csk phosphorylation of Fyn-inhibitory COOH-terminal Y531 (yellow). After axonal contact and ligation by α6β1 of the α2 chain laminins expressed in myelinating axon tracts, Lyn dissociates from the integrin–growth factor complex and Csk is downregulated, reducing Fyn phosphorylation at Y531 and promoting Fyn activity. Active Fyn–α6β1 complexes can then trigger PI3K and MAPK signaling, depending on the ligand binding of PDGFαR and ErbB2/4 receptors, respectively, thereby promoting oligodendrocyte survival, differentiation, and myelin formation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172535&req=5

fig9: Model for integrin regulation of SFK activity during oligodendrocyte lineage progression. In oligodendrocyte progenitors, Lyn is associated with the PDGFαR–αVβ3 integrin complex and contributes to proliferation signaling. Catalytic Y397 of Lyn (orange) is phosphorylated after αVβ3 integrin ligation. Fyn is maintained in the inactive state by Csk phosphorylation of Fyn-inhibitory COOH-terminal Y531 (yellow). After axonal contact and ligation by α6β1 of the α2 chain laminins expressed in myelinating axon tracts, Lyn dissociates from the integrin–growth factor complex and Csk is downregulated, reducing Fyn phosphorylation at Y531 and promoting Fyn activity. Active Fyn–α6β1 complexes can then trigger PI3K and MAPK signaling, depending on the ligand binding of PDGFαR and ErbB2/4 receptors, respectively, thereby promoting oligodendrocyte survival, differentiation, and myelin formation.
Mentions: Myelinating oligodendrocytes provide a model system for understanding how ECM and growth factors regulate distinct aspects of cell behavior during development. We have shown previously that changing interactions between integrins and growth factor receptors within the membrane provide a mechanism for temporal and spatial specificity of growth factor signaling. Here, we identify the SFKs Fyn and Lyn as key effector molecules within these integrin–growth factor receptor complexes that selectively promote either proliferation or differentiation/survival. As such, they serve both to integrate the extracellular signals provided by ECM and growth factors and to translate these signals into specific cell behaviors during development. The illustration in Fig. 9 summarizes how these different integrins regulate distinct phases of the oligodendrocyte lineage by using distinct SFK partners and thereby ensuring correct timing and location for oligodendrocyte proliferation, survival, and, ultimately, myelin formation. In this model, the key association necessary for the specificity of each SFK is with the integrin, rather than with the growth factor receptor. In support of this, a role for SFKs in integrin signaling is well established, whereas a link between SFK signaling and PDGFαR signaling remains less clear. Triple gene knockouts revealed that Src, Yes, and Fyn were dispensable for PDGF-mediated signaling in fibroblasts, but necessary for several ECM-mediated functions (Klinghoffer et al., 1999). And, although PDGF deficiency leads to hypomyelination during development, this defect occurs in regions of the central nervous system that are unaffected in Fyn −/− mice (Fruttiger et al., 1999). Together, these findings are consistent with a model in which growth factor stimulation in the absence of integrin ligation is not sufficient to activate a requirement for SFK.

Bottom Line: Specific integrins expressed on oligodendrocytes, the myelin-forming cells of the central nervous system, promote either differentiation and survival or proliferation by amplification of growth factor signaling.Fyn associates with alpha6beta1 and is required to amplify platelet-derived growth factor survival signaling, to promote myelin membrane formation, and to switch neuregulin signaling from a phosphatidylinositol 3-kinase to a mitogen-activated protein kinase pathway (thereby changing the response from proliferation to differentiation).However, earlier in the lineage Lyn, not Fyn, is required to drive alphaVbeta3-dependent progenitor proliferation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Cambridge, Cambridge CB21QP, England, UK. colognato@pharm.sunysb.edu

ABSTRACT
Specific integrins expressed on oligodendrocytes, the myelin-forming cells of the central nervous system, promote either differentiation and survival or proliferation by amplification of growth factor signaling. Here, we report that the Src family kinases (SFKs) Fyn and Lyn regulate each of these distinct integrin-driven behaviors. Fyn associates with alpha6beta1 and is required to amplify platelet-derived growth factor survival signaling, to promote myelin membrane formation, and to switch neuregulin signaling from a phosphatidylinositol 3-kinase to a mitogen-activated protein kinase pathway (thereby changing the response from proliferation to differentiation). However, earlier in the lineage Lyn, not Fyn, is required to drive alphaVbeta3-dependent progenitor proliferation. The two SFKs respond to integrin ligation by different mechanisms: Lyn, by increased autophosphorylation of a catalytic tyrosine; and Fyn, by reduced Csk phosphorylation of the inhibitory COOH-terminal tyrosine. These findings illustrate how different SFKs can act as effectors for specific cell responses during development within a single cell lineage, and, furthermore, provide a molecular mechanism to explain similar region-specific hypomyelination in laminin- and Fyn-deficient mice.

Show MeSH
Related in: MedlinePlus