Transmembrane-4 superfamily proteins associate with activated protein kinase C (PKC) and link PKC to specific beta(1) integrins

J Biol Chem. 2001 Jul 6;276(27):25005-13. doi: 10.1074/jbc.M102156200. Epub 2001 Apr 26.


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 (alpha(3)beta(1), alpha(6)beta(1), and a chimeric "X3TC5" alpha(3) 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 alpha(3) subunit and to intracellular PKC helps to explain why the integrin alpha3 extracellular domain is needed for both intracellular PKC recruitment and PKC-dependent phosphorylation of the alpha(3) integrin cytoplasmic tail.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens, CD / chemistry
  • Antigens, CD / metabolism*
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • Blotting, Western
  • CD3 Complex / metabolism
  • Enzyme Activation
  • Fluorescent Antibody Technique
  • Goats
  • Humans
  • Integrin alpha3
  • Integrin alpha3beta1
  • Integrin alpha6beta1
  • Integrin beta1 / metabolism*
  • Integrins / chemistry
  • Integrins / metabolism
  • Jurkat Cells
  • Membrane Glycoproteins*
  • Membrane Proteins*
  • Mice
  • Protein Conformation
  • Protein Kinase C / metabolism*
  • Tetraspanin 24
  • Tetraspanin 25
  • Tetraspanin 28
  • Tetraspanin 29
  • Tumor Cells, Cultured


  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD151 protein, human
  • CD3 Complex
  • CD53 protein, human
  • CD81 protein, human
  • CD9 protein, human
  • Cd151 protein, mouse
  • Cd53 protein, mouse
  • Cd81 protein, mouse
  • Cd9 protein, mouse
  • Integrin alpha3
  • Integrin alpha3beta1
  • Integrin alpha6beta1
  • Integrin beta1
  • Integrins
  • Membrane Glycoproteins
  • Membrane Proteins
  • Tetraspanin 24
  • Tetraspanin 25
  • Tetraspanin 28
  • Tetraspanin 29
  • Protein Kinase C