The Dbl oncogene product was originally identified as the transforming gene from human diffuse B- cell lymphoma. It is now evident that Dbl is only one member of a growing family of cellular proteins that contain a unique structural 'signature': the tandem arrangement of pleckstrin homology (PH) and Dbl homology (DH) domains. Mutated versions of most DbI- like genes were identified as causing a variety of human malignant and invasive pathologies, suggesting a key role for these molecules in regulation of normal cell growth. To date, only one biochemical activity has been associated with Dbl- related proteins, namely to serve activators of (cause GTP binding to) low Mw GTP- binding proteins from the Rho- subfamily, such as Rho, Cdc42 and Rac. It is generally hypothesized that the basis for the oncogenic capability exhibited by Dbl molecules is an outcome of their ability to cause GTPase activation. In accordance with this hypothesis, activated alleles of Cdc42, Rac and Rho proteins were demonstrated to possess growth- regulatory properties. The proposed research aims at gaining a better understanding of the molecular mechanisms that underlie Dbl- induced transformation of mammalian cells. Two specific avenues of investigation will be pursued that constitute the specific aims of this proposal.
These aims are: 1) To understand how the activity of proto- Dbl is regulated in normal (non-transformed) cells. We propose to address the roles of interacting proteins, intra-cellular localization and phosphorylation events in regulating the growth- promoting signals originating from proto- Dbl. 2) To understand the down-stream signaling pathway that leads from activation of Cdc42 by Dbl to oncogenic transformation. We propose to identify a novel target of Cdc42 that is a likely candidate for mediating Dbl- transformation signals and to characterize the signaling pathway that originates from Dbl and leads to stimulation of survival pathways via activation of PDK1 and Akt.
| Gupta, Meghana; Qi, Xiaojun; Thakur, Varsha et al. (2014) Tyrosine phosphorylation of Dbl regulates GTPase signaling. J Biol Chem 289:17195-202 |
| Gupta, Meghana; Kamynina, Elena; Morley, Samantha et al. (2013) Plekhg4 is a novel Dbl family guanine nucleotide exchange factor protein for rho family GTPases. J Biol Chem 288:14522-30 |
