QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 17, Issue 9, 3717-3728, September 2006

This Article Full Text Full Text (PDF) All Versions of this Article: E06-03-0244v1 17/9/3717    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mood, K. Articles by Daar, I. O. Search for Related Content PubMed PubMed Citation Articles by Mood, K. Articles by Daar, I. O.

Gab1 Is Required for Cell Cycle Transition, Cell Proliferation, and Transformation Induced by an Oncogenic Met Receptor

Kathleen Mood^*,, Caroline Saucier^,, Yong-Sik Bong^*, Hyun-Shik Lee^*, Morag Park^,, and Ira O. Daar^*

*Laboratory of Protein Dynamics and Signaling, National Cancer Institute-Frederick, Frederick, MD 21702; and Molecular Oncology Group and Departments of Biochemistry, Medicine, and Oncology, McGill University Health Center, Montreal, Quebec, Canada H3A 1A1

Submitted March 28, 2006; Revised April 18, 2006; Accepted June 2, 2006
Monitoring Editor: Gerard Evan

We have shown previously that either Grb2- or Shc-mediated signaling from the oncogenic Met receptor Tpr-Met is sufficient to trigger cell cycle progression in Xenopus oocytes. However, direct binding of these adaptors to Tpr-Met is dispensable, implying that another Met binding partner mediates these responses. In this study, we show that overexpression of Grb2-associated binder 1 (Gab1) promotes cell cycle progression when Tpr-Met is expressed at suboptimal levels. This response requires that Gab1 possess an intact Met-binding motif, the pleckstrin homology domain, and the binding sites for phosphatidylinositol 3-kinase and tyrosine phosphatase SHP-2, but not the Grb2 and CrkII/phospholipase C binding sites. Importantly, we establish that Gab1-mediated signals are critical for cell cycle transition promoted by the oncogenic Met and fibroblast growth factor receptors, but not by progesterone, the natural inducer of cell cycle transition in Xenopus oocytes. Moreover, Gab1 is essential for Tpr-Met–mediated morphological transformation and proliferation of fibroblasts. This study provides the first evidence that Gab1 is a key binding partner of the Met receptor for induction of cell cycle progression, proliferation, and oncogenic morphological transformation. This study identifies Gab1 and its associated signaling partners as potential therapeutic targets to impair proliferation or transformation of cancer cells in human malignancies harboring a deregulated Met receptor.

These authors contributed equally to this work.

Address correspondence to: Ira O. Daar (daar{at}ncifcrf.gov)

Abbreviations used: Gab1, Grb2-associated binder 1; GVBD, germinal vesicle breakdown; MBD, Met-binding domain; MBM, Met-binding motif; RTK, receptor tyrosine kinase.

This article has been cited by other articles:

				I. Seiden-Long, R. Navab, W. Shih, M. Li, J. Chow, C. Q. Zhu, N. Radulovich, C. Saucier, and M.-S. Tsao Gab1 but not Grb2 mediates tumor progression in Met overexpressing colorectal cancer cells Carcinogenesis, March 1, 2008; 29(3): 647 - 655. [Abstract] [Full Text] [PDF]

				U. Schaeper, R. Vogel, J. Chmielowiec, J. Huelsken, M. Rosario, and W. Birchmeier Distinct requirements for Gab1 in Met and EGF receptor signaling in vivo PNAS, September 25, 2007; 104(39): 15376 - 15381. [Abstract] [Full Text] [PDF]