STK/RON receptor tyrosine kinase mediates both apoptotic and growth signals via the multifunctional docking site conserved among the HGF receptor family

Atsushi Iwama, Naoto Yamaguchi, Toshio Suda

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

STK/RON tyrosine kinase, a member of the hepatocyte growth factor (HGF) receptor family, is a receptor for macrophage-stimulating protein (MSP). To examine the STK/RON signalling pathway, we generated STK/RON transfectants showing opposite features in growth. STK/RON-expressing Ba/F3 pro-B cells (BaF/STK) exhibited MSP-dependent growth, whereas STK/ RON-expressing mouse erythroleukaemia cells (MEL/STK) displayed MSP-induced apoptosis. This apoptosis was accompanied by the prolonged activation of c-Jun N-terminal kinase (JNK), which has recently been implicated in the initiation of apoptosis. Co-immunoprecipitation analyses showed that autophosphorylated STK/RON associated with PLC-γ, PI3-kinase, Shc and Grb2 in both transfectants. However, major tyrosine-phosphorylated proteins, p61 and p65, specifically associated with STK/RON in MEL/STK cells. Mutations at two C-terminal tyrosine residues, Y1330 and Y1337, in the counterpart of the multifunctional docking site of the HGF receptor abolished both MSPinduced growth and apoptosis. Analyses of these mutants and in vitro association revealed that signalling proteins including p61 and p65 directly bound to the phosphotyrosines in the multifunctional docking site. These results demonstrate that positive or negative signals toward cell growth are generated through the multifunctional docking site and suggest the involvement of p61 and p65 as well as JNK in apoptosis. Our findings provide the first evidence for apoptosis via a receptor tyrosine kinase.

Original languageEnglish
Pages (from-to)5866-5875
Number of pages10
JournalEMBO Journal
Volume15
Issue number21
Publication statusPublished - 1996 Nov 1

Fingerprint

Proto-Oncogene Proteins c-met
Receptor Protein-Tyrosine Kinases
Apoptosis
Growth
JNK Mitogen-Activated Protein Kinases
Tyrosine
Leukemia, Erythroblastic, Acute
Phosphotyrosine
B-Lymphoid Precursor Cells
Cell growth
Programmable logic controllers
rice bran saccharide
Phosphatidylinositol 3-Kinases
Immunoprecipitation
Protein-Tyrosine Kinases
Proteins
Chemical activation
Cells
Association reactions
Mutation

Keywords

  • Apoptosis
  • c-Jun N-terminal kinase
  • Macrophage-stimulating protein
  • Receptor tyrosine kinase
  • STK/RON

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

STK/RON receptor tyrosine kinase mediates both apoptotic and growth signals via the multifunctional docking site conserved among the HGF receptor family. / Iwama, Atsushi; Yamaguchi, Naoto; Suda, Toshio.

In: EMBO Journal, Vol. 15, No. 21, 01.11.1996, p. 5866-5875.

Research output: Contribution to journalArticle

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abstract = "STK/RON tyrosine kinase, a member of the hepatocyte growth factor (HGF) receptor family, is a receptor for macrophage-stimulating protein (MSP). To examine the STK/RON signalling pathway, we generated STK/RON transfectants showing opposite features in growth. STK/RON-expressing Ba/F3 pro-B cells (BaF/STK) exhibited MSP-dependent growth, whereas STK/ RON-expressing mouse erythroleukaemia cells (MEL/STK) displayed MSP-induced apoptosis. This apoptosis was accompanied by the prolonged activation of c-Jun N-terminal kinase (JNK), which has recently been implicated in the initiation of apoptosis. Co-immunoprecipitation analyses showed that autophosphorylated STK/RON associated with PLC-γ, PI3-kinase, Shc and Grb2 in both transfectants. However, major tyrosine-phosphorylated proteins, p61 and p65, specifically associated with STK/RON in MEL/STK cells. Mutations at two C-terminal tyrosine residues, Y1330 and Y1337, in the counterpart of the multifunctional docking site of the HGF receptor abolished both MSPinduced growth and apoptosis. Analyses of these mutants and in vitro association revealed that signalling proteins including p61 and p65 directly bound to the phosphotyrosines in the multifunctional docking site. These results demonstrate that positive or negative signals toward cell growth are generated through the multifunctional docking site and suggest the involvement of p61 and p65 as well as JNK in apoptosis. Our findings provide the first evidence for apoptosis via a receptor tyrosine kinase.",
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