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Caspase-mediated Cleavage of the TIAM1 Guanine Nucleotide Exchange Factor during Apoptosis¹

University of Pennsylvania School of Medicine, Department of Cell and Developmental Biology [H. Q., M. M. C.], Department of Pharmacology [J. M-R., H. Z., N. S.], and Center for Experimental Medicine and Department of Pharmacology [M. J. C., M. G. K.], Philadelphia, Pennsylvania 19104-6160, and Department of Molecular and Cell Biology, University of California-Berkeley, Berkeley, California 94720 [P. J.]

Rho family GTPases Rac and Cdc42 are pivotal regulators of apoptosis in multiple cell types. However, little is known about the mechanism by which these GTPases are regulated in response to apoptotic stimuli. Here, we demonstrate that TIAM1, a Rac-specific guanine nucleotide exchange factor, is cleaved by caspases during apoptosis. TIAM1 cleavage occurs in multiple cell lines in response to diverse apoptotic stimuli such as ceramide, Fas, and serum deprivation. Processing occurs at residue 993 of TIAM1 and removes the NH₂-terminal of TIAM’s two pleckstrin homology domains, leaving a stable fragment containing the Dbl homology and COOH-terminal pleckstrin homology domains. This leads to functional inactivation of TIAM1, as determined by failure of the cleavage product to stimulate GTP loading of Rac in vivo. Furthermore, this product is defective in signaling to two independent Rac effectors, c-Jun NH₂-terminal kinase and serum response factor. Finally, we demonstrate that in cells treated with ceramide, cleavage of TIAM1 coincided with the inactivation of endogenous Rac. These results reveal a novel mechanism for regulating guanine nucleotide exchange factor activity and GTPase-mediated signaling pathways.

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