Sprouty (SPRY) proteins modulate receptor-tyrosine kinase signaling and, thereby, regulate cell migration and proliferation. Here, we have examined the role of endogenous human SPRY2 (hSPRY2) in the regulation of cellular apoptosis. Small inhibitory RNA-mediated silencing of hSPRY2 abolished the anti-apoptotic action of serum in adrenal cortex adenocarcinoma (SW13) cells. Silencing of hSPRY2 decreased serum- or epidermal growth factor (EGF)-elicited activation of AKT and ERK1/2 and reduced the levels of EGF receptor. Silencing of hSPRY2 also inhibited serum-induced activation of p90RSK and decreased phosphorylation of pro-apoptotic protein BAD (BCL2-antagonist of cell death) by p90RSK. Inhibiting both the ERK1/2 and AKT pathways abolished the ability of serum to protect against apoptosis, mimicking the effects of silencing hSPRY2. Serum transactivated the EGF receptor (EGFR), and inhibition of the EGFR by a neutralizing antibody attenuated the anti-apoptotic actions of serum. Consistent with the role of EGFR and perhaps other growth factor receptors in the anti-apoptotic actions of serum, the tyrosine kinase binding domain of c-Cbl (Cbl-TKB) protected against down-regulation of the growth factor receptors such as EGFR and preserved the anti-apoptotic actions of serum when hSpry2 was silenced. Additionally, silencing of Spry2 in c-Cbl null cells did not alter the ability of serum to promote cell survival. Moreover, reintroduction of wild type hSPRY2, but not its mutants that do not bind c-Cbl or CIN85 into SW13 cells after endogenous hSPRY2 had been silenced, restored the anti-apoptotic actions of serum. Overall, we conclude that endogenous hSPRY2-mediated regulation of apoptosis requires c-Cbl and is manifested by the ability of hSPRY2 to sequester c-Cbl and thereby augment signaling via growth factor receptors.