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J Biol Chem, Vol. 274, Issue 43, 30410-30418, October 22, 1999

Involvement of NH₂-terminal Sequences in the Negative Regulation of Vav Signaling and Transforming Activity

From the Department of Pharmacology, University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599

Deletion of the NH₂-terminal 65 amino acids of proto-Vav (to form onco-Vav) activates its transforming activity, suggesting that these sequences serve a negative regulatory role in Vav function. However, the precise role of these NH₂-terminal sequences and whether additional NH₂-terminal sequences are also involved in negative regulation have not been determined. Therefore, we generated additional NH₂-terminal deletion mutants of proto-Vav that lack the NH₂-terminal 127, 168, or 186 amino acids, and assessed their abilities to cause focus formation in NIH 3T3 cells and to activate different signaling pathways. Since Vav mutants lacking 168 or 186 NH₂-terminal residues showed a several 100-fold greater focus forming activity than that seen with deletion of 65 residues, residues spanning 66 to 187 also contribute significantly to negative regulation of Vav transforming activity. The increase in Vav transforming activity correlated with the activation of the c-Jun, Elk-1, and NF-B transcription factors, as well as increased transcription from the cyclin D1 promoter. Tyrosine 174 is a key site of phosphorylation by Lck in vitro and Lck-mediated phosphorylation has been shown to be essential for proto-Vav GEF function in vitro. However, we found that an NH₂-terminal Vav deletion mutant lacking this tyrosine residue (N-186 Vav) retained the ability to be phosphorylated by Lck in vivo and Lck still caused enhancement of N-186 Vav signaling and transforming activity. Thus, Lck can stimulate Vav via a mechanism that does not involve Tyr¹⁷⁴ or removal of NH₂-terminal regulatory activity. Finally, we found that NH₂-terminal deletion enhanced the degree of Vav association with the membrane-containing particulate fraction and that an isolated NH₂-terminal fragment (residues 1-186) could impair N-186 Vav signaling. Taken together, these observations suggest that the NH₂ terminus may serve as a negative regulator of Vav by intramolecular interaction with COOH-terminal sequences to modulate efficient membrane association.

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