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Blood, 15 February 2002, Vol. 99, No. 4, pp. 1388-1397
NEOPLASIA
Regulation of the Erk2-Elk1 signaling pathway and megakaryocytic
differentiation of Bcr-Abl+ K562 leukemic cells by
Gab2
Jay F. Dorsey,
Jess M. Cunnick,
Shrikant M. Mane, and
Jie Wu
From the Molecular Oncology Program, H. Lee Moffitt
Cancer Center and Research Institute, Tampa, FL, and the Departments of
Interdisciplinary Oncology and Medical Microbiology and Immunology,
University of South Florida, Tampa.
In the blast crisis phase of chronic myelogenous leukemia (CML),
Bcr-Abl+ myeloblasts fail to undergo terminal maturation.
The extracellular signal-regulated kinase (Erk) mitogen-activated
protein (MAP) kinase has been shown to mediate terminal differentiation
of myeloid cells. Interestingly, Bcr-Abl+ CML cell lines
established from blast crisis were found to have low Erk MAP kinase
activity. In this study, we analyzed the role of the Gab2 docking
protein in regulation of the Erk MAP kinase in Bcr-Abl+
K562 human CML cells. Overexpression of Gab2 in K562 cells resulted in
transcriptional activation of the c-fos serum response
element (SRE) promoter, whereas overexpression of SHP2, Grb2, and CrkL had no effect. Activation of the c-fos SRE transcriptional
activity by Gab2 required tyrosine 604, which is a SHP2 docking site on Gab2, and the SHP2 tyrosine phosphatase activity. Elk1, c-Jun, and CHOP
trans-reporting assays indicated that overexpression of
Gab2 selectively activated the Erk2-Elk1 signaling pathway. To
determine cellular consequences of elevating the Gab2 level in K562
cells, stable cell lines for doxycycline-inducible expression of the
wild-type Gab2 (Gab2WT) and an SHP2-binding defective Gab2 (Gab2Tyr604Phe) were established. Analysis of these cell lines indicated that induction of Gab2WT expression, but not Gab2Tyr604Phe expression, led to Erk activation, growth arrest, cell spreading, and
enlargement; expression of megakaryocyte/platelet lineage-specific integrins  IIb/ 3 (CD41/CD61); and upregulation of RNA for
megakaryocyte/platelet proteins. All of these changes are
characteristics of megakaryocytic differentiation. Together, these
results reveal Gab2 as a limiting signaling component for Erk MAP
kinase activation and terminal differentiation of K562 CML cells.
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