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Gab1 phosphorylation: a novel mechanism for negative regulation of HGF receptor signaling

Oncogene volume 20, pages 156–166 (2001)Cite this article

Abstract

Signal transduction by HGF receptor, the tyrosine kinase encoded by the MET oncogene, switches on a genetic program called ‘invasive growth’ inducing epithelial cell dissociation, migration, growth, and ultimately leading to differentiation into branched tubular structures. Sustained tyrosine phosphorylation of the downstream adaptor protein Gab1 is required for the HGF response. Here we show that serine/threonine phosphorylation of Gab1 provides a control mechanism for negative regulation. Treatment with okadaic acid, a potent inhibitor of the serine/threonine protein phosphatases PP1 and PP2A, was followed by activation of a number of serine/threonine kinases, hyper-phosphorylation in serine and threonine of Gab1 and severe inhibition of the HGF-induced biological responses. Under these conditions, Gab1 was found to be concomitantly hypo-phosphorylated in tyrosine, and thus endowed with reduced ability to recruit SH2 containing signal transducers such as PI3 kinase. Among the serine-threonine kinases activated by PP1 and PP2A inhibition, we found that PKC-α and PKC-β1 are required for negative regulation of Gab1. These data provide a novel negative mechanism for the HGF receptor signaling pathways and highlight a potentially useful target for inhibitors of invasive growth.

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Abbreviations

PKC:

Protein Kinase C

HGF:

hepatocyte growth factor

GRB-2:

growth factor receptor-bound protein 2

Gab1:

GRB2 associated binder-1

PI 3 kinase:

phosphoinositide 3 kinase

STAT:

signal transducer and activator of the transcription

SHPTP:

SH2 containing Phosphotyrosine phosphatase

SHC:

Src homology/collagen

SH2:

Src homology 2

p85:

the 85 kDa regulatory subunit of PI 3 kinase

pr:

precursor

GST:

glutathione S-transferase

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Acknowledgements

We are grateful to Dr W Birchmeier for mouse Gab1 cDNA. The excellent technical assistance of L Palmas, R Albano and G Petruccelli is gratefully acknowledged. We thank Antonella Cignetto for secretarial help and Elaine Wright for editing the manuscript. This work was supported by BIOMED EC grant no. BMH4-CT983852 to PM Comoglio. P Gual is supported by Marie Curie TMR fellowships.

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Authors and Affiliations

  1. Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, Str. Prov. 142, Km 3.95, Candiolo, 10060, Italy

    P Gual, S Giordano, S Anguissola & PM Comoglio

  2. Protein Phosphorylation Laboratory, Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK

    PJ Parker

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Gual, P., Giordano, S., Anguissola, S. et al. Gab1 phosphorylation: a novel mechanism for negative regulation of HGF receptor signaling. Oncogene 20, 156–166 (2001). https://doi.org/10.1038/sj.onc.1204047

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