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J. Biol. Chem., Vol. 276, Issue 2, 1494-1502, January 12, 2001

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Tyrosine Phosphorylation of the ₄ Integrin Cytoplasmic Domain Mediates Shc Signaling to Extracellular Signal-regulated Kinase and Antagonizes Formation of Hemidesmosomes^*

Michael Dans, Laurent Gagnoux-Palacios^§, Pamela Blaikie, Sharon Klein^¶, Agnese Mariotti, and Filippo G. Giancotti

From the Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Ligation of the ₆₄ integrin induces tyrosine phosphorylation of the ₄ cytoplasmic domain, followed by recruitment of the adaptor protein Shc and activation of mitogen-activated protein kinase cascades. We have used Far Western analysis and phosphopeptide competition assays to map the sites in the cytoplasmic domain of ₄ that are required for interaction with Shc. Our results indicate that, upon phosphorylation, Tyr¹⁴⁴⁰, or secondarily Tyr¹⁴²², interacts with the SH2 domain of Shc, whereas Tyr¹⁵²⁶, or secondarily Tyr¹⁶⁴², interacts with its phosphotyrosine binding (PTB) domain. An inactivating mutation in the PTB domain of Shc, but not one in its SH2 domain, suppresses the activation of Shc by ₆₄. In addition, mutation of ₄ Tyr¹⁵²⁶, which binds to the PTB domain of Shc, but not of Tyr¹⁴²² and Tyr¹⁴⁴⁰, which interact with its SH2 domain, abolishes the activation of ERK by ₆₄. Phenylalanine substitution of the ₄ tyrosines able to interact with the SH2 or PTB domain of Shc does not affect incorporation of ₆₄ in the hemidesmosomes of 804G cells. Exposure to the tyrosine phosphatase inhibitor orthovanadate increases tyrosine phosphorylation of 4 and disrupts the hemidesmosomes of 804G cells expressing recombinant wild type ₄. This treatment, however, exerts a decreasing degree of inhibition on the hemidesmosomes of cells expressing versions of ₄ containing phenylalanine substitutions at Tyr¹⁴²² and Tyr¹⁴⁴⁰, at Tyr¹⁵²⁶ and Tyr¹⁶⁴², or at all four tyrosine phosphorylation sites. These results suggest that ₄ Tyr¹⁵²⁶ interacts in a phosphorylation-dependent manner with the PTB domain of Shc. This event is required for subsequent tyrosine phosphorylation of Shc and signaling to ERK but not formation of hemidesmosomes.

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