MEMBRANE TRANSPORT STRUCTURE FUNCTION AND BIOGENESIS
Transmembrane-4 Superfamily Proteins Associate with Activated Protein Kinase C (PKC) and Link PKC to Specific β1 Integrins*

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Translocation of conventional protein kinases C (PKCs) to the plasma membrane leads to their specific association with transmembrane-4 superfamily (TM4SF; tetraspanin) proteins (CD9, CD53, CD81, CD82, and CD151), as demonstrated by reciprocal co-immunoprecipitation and covalent cross-linking experiments. Although formation and maintenance of TM4SF-PKC complexes are not dependent on integrins, TM4SF proteins can act as linker molecules, recruiting PKC into proximity with specific integrins. Previous studies showed that the extracellular large loop of TM4SF proteins determines integrin associations. In contrast, specificity for PKC association probably resides within cytoplasmic tails or the first two transmembrane domains of TM4SF proteins, as seen from studies with chimeric CD9 molecules. Consistent with a TM4SF linker function, only those integrins (α3β1, α6β1, and a chimeric “X3TC5” α3 mutant) that associated strongly with tetraspanins were found in association with PKC. We propose that PKC-TM4SF-integrin structures represent a novel type of signaling complex. The simultaneous binding of TM4SF proteins to the extracellular domains of the integrin α3 subunit and to intracellular PKC helps to explain why the integrin α3 extracellular domain is needed for both intracellular PKC recruitment and PKC-dependent phosphorylation of the α3 integrin cytoplasmic tail.

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Published, JBC Papers in Press, April 26, 2001, DOI 10.1074/jbc.M102156200

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This work was supported by National Institutes of Health Grant CA86712 (to M. E. H.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Vascular Biology Center, University of Tennessee Health Science Center, Memphis, TN 38163.