The germinal center kinase (GCK)-related protein kinases HPK1 and KHS are candidates for highly selective signal transducers of Crk family adapter proteins

Oncogene. 1998 Oct 15;17(15):1893-901. doi: 10.1038/sj.onc.1202108.

Abstract

Adapter proteins function by mediating the rapid and specific assembly of multi-protein complexes during the signal transduction which guards proliferation, differentiation and many functions of higher eukaryotic cells. To understand their functional roles in different cells it is important to identify the selectively interacting proteins in these cells. Two novel candidates for signalling partners of Crk family adapter proteins, the hematopoietic progenitor kinase 1 (HPK1) and the kinase homologous to SPS1/STE20 (KHS), were found to bind with great selectivity to the first SH3 domains of c-Crk and CRKL. While KHS bound exclusively to Crk family proteins, HPK1 also interacted with both SH3 domains of Grb2 and weakly with Nck, but not with more than 25 other SH3 domains tested. The interaction of HPK1 with c-Crk and CRKL was studied in more detail. HPK1-binding to the first SH3 domain of CRKL is direct and occurs via proline-rich motifs in the C-terminal, non-catalytic portion of HPK1. In vitro complexes were highly stable and in vivo complexes of c-Crk and CRKL with HPK1 were detectable by co-immunoprecipitation with transiently transfected cells but also with endogenous proteins. Furthermore, c-Crk II and, to a lesser extent, CRKL were substrates for HPK1. These results make it likely that HPK1 and KHS participate in the signal transduction of Crk family adapter proteins in certain cell types.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Chick Embryo
  • Consensus Sequence
  • Enzyme Activation
  • GRB2 Adaptor Protein
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Proline / metabolism
  • Protein Binding
  • Protein Serine-Threonine Kinases / metabolism*
  • Proteins / metabolism
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-crk
  • Signal Transduction*
  • src Homology Domains

Substances

  • Adaptor Proteins, Signal Transducing
  • CRKL protein
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-crk
  • Proline
  • hematopoietic progenitor kinase 1
  • Protein Serine-Threonine Kinases
  • STK25 protein, human