Critical role for hematopoietic cell kinase (Hck)-mediated phosphorylation of Gab1 and Gab2 docking proteins in interleukin 6-induced proliferation and survival of multiple myeloma cells.

Abstract

Interleukin-6 (LI-6) is a known growth and survival factor in multiple myeloma via activation of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling cascade. In this report we show that Grb2-associated binder (Gab) family adapter proteins Gab1 and Gab2 are expressed by multiple myeloma cells; and that interleukin-6 induces their tyrosine phosphorylation and association with downstream signaling molecules. We further demonstrate that these events are Src family tyrosine kinase-dependent and specifically identify the role of hematopoietic cell kinase (Hck) as a new Gab family adapter protein kinase. Conversely, inhibition of Src family tyrosine kinases by the pyrazolopyrimidine PP2, as in kinase-inactive Hck mutants, significantly reduces IL-6-triggered activation of extracellular signal-regulated kinase and AKT-1, leading to significant reduction of multiple myeloma cell proliferation and survival. Taken together, these results delineate a key role for Hck-mediated phosphorylation of Gab1 and Gab2 docking proteins in IL-6-induced proliferation and survival of multiple myeloma cells and identify tyrosine kinases and downstream adapter proteins as potential new therapeutic targets in multiple myeloma.

• Authors: Klaus Podar, Gustavo Mostoslavsky, Martin Sattler, Yu-Tzu Tai, Toshiaki Hayashi, Laurence P Catley, Teru Hideshima, Richard C Mulligan, Dharminder Chauhan, Kenneth C Anderson
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 279 Issue 20 Pg. 21658-65 (May 14 2004) ISSN: 0021-9258 [Print] United States
• PMID: 15010462 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adaptor Proteins, Signal Transducing
• GAB2 protein, human
• Interleukin-6
• Phosphoproteins
• Proto-Oncogene Proteins
• Recombinant Proteins
• Phosphotyrosine
• Protein-Tyrosine Kinases
• HCK protein, human
• Proto-Oncogene Proteins c-hck

Topics

• Adaptor Proteins, Signal Transducing
• Cell Division
• Cell Line, Tumor
• Cell Survival
• Humans
• Interleukin-6 (pharmacology)
• Multiple Myeloma (enzymology, pathology)
• Mutagenesis
• Phosphoproteins (metabolism)
• Phosphorylation
• Phosphotyrosine (metabolism)
• Protein-Tyrosine Kinases (genetics, metabolism)
• Proto-Oncogene Proteins (genetics, metabolism)
• Proto-Oncogene Proteins c-hck
• Recombinant Proteins (metabolism, pharmacology)
• Signal Transduction