Neuronal Thy-1 induces astrocyte adhesion by engaging syndecan-4 in a cooperative interaction with alphavbeta3 integrin that activates PKCalpha and RhoA

J Cell Sci. 2009 Oct 1;122(Pt 19):3462-71. doi: 10.1242/jcs.034827. Epub 2009 Sep 1.

Abstract

Clustering of alphavbeta3 integrin after interaction with the RGD-like integrin-binding sequence present in neuronal Thy-1 triggers formation of focal adhesions and stress fibers in astrocytes via RhoA activation. A putative heparin-binding domain is present in Thy-1, raising the possibility that this membrane protein stimulates astrocyte adhesion via engagement of an integrin and the proteoglycan syndecan-4. Indeed, heparin, heparitinase treatment and mutation of the Thy-1 heparin-binding site each inhibited Thy-1-induced RhoA activation, as well as formation of focal adhesions and stress fibers in DI TNC(1) astrocytes. These responses required both syndecan-4 binding and signaling, as evidenced by silencing syndecan-4 expression and by overexpressing a syndecan-4 mutant lacking the intracellular domain, respectively. Furthermore, lack of RhoA activation and astrocyte responses in the presence of a PKC inhibitor or a dominant-negative form of PKCalpha implicated PKCalpha and RhoA activation in these events. Therefore, combined interaction of the astrocyte alphavbeta3-integrin-syndecan-4 receptor pair with Thy-1, promotes adhesion to the underlying matrix via PKCalpha- and RhoA-dependent pathways. Importantly, signaling events triggered by such receptor cooperation are shown here to be the consequence of cell-cell rather than cell-matrix interactions. These observations are likely to be of widespread biological relevance because Thy-1-integrin binding is reportedly relevant to melanoma invasion, monocyte transmigration through endothelial cells and host defense mechanisms.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Astrocytes / chemistry
  • Astrocytes / metabolism*
  • Cell Adhesion
  • Cell Line
  • Enzyme Activation
  • Humans
  • Integrin alphaVbeta3 / genetics
  • Integrin alphaVbeta3 / metabolism*
  • Molecular Sequence Data
  • Neurons / chemistry
  • Neurons / metabolism*
  • Protein Binding
  • Protein Kinase C-alpha / genetics
  • Protein Kinase C-alpha / metabolism*
  • Protein Structure, Tertiary
  • Rats
  • Sequence Alignment
  • Signal Transduction
  • Syndecan-4 / genetics
  • Syndecan-4 / metabolism*
  • Thy-1 Antigens / chemistry
  • Thy-1 Antigens / genetics
  • Thy-1 Antigens / metabolism*
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • Integrin alphaVbeta3
  • Syndecan-4
  • Thy-1 Antigens
  • Protein Kinase C-alpha
  • rhoA GTP-Binding Protein