Extracellular signal-regulated kinase-5 (ERK5) (previously known as BMK1) is an atypical MAP kinase. The exact role of ERK5 remains unknown however it is critically important in cell survival and differentiation as highlighted by the embryonic lethality of the ERK5 knock-out (Yan et al., 2003). ERK5 possess a transactivation domain and may act as a transcriptional coactivator by recruiting basal transcriptional machinery. ERK5 has been shown to induce its translocation to the nucleus, where it can activate the transcription factor, Myocyte enhancing factor-2C (MEF2C), inducing c-Jun expression (Kato et al. 1997). Hence the functions of MEF2 could be regulated through ERK5. ERK5 has been shown to be anti-apoptotic in endothelial cells (Pi et al. 2004) and to mediate the survival of neurones in the CNS via the activation of MEF2 (Liu et al., 2003; Shalizi et al. 2003). Inhibitors of the ERK1/2 pathway (PD 98059 or UO126) have been reported to inhibit ERK5. However previously we have shown that neither inhibitor reduce EGF-induced ERK5 in proximal tubule epithelial cells (PTECs). We therefore used siRNA to selectively knock down ERK5 and investigate the role of ERK5 in PTEC apoptosis. Lysates of HKC-8 cells treated for 5 min with either EGF (10ng/ml) or vehicle (0.1% BSA) were used for Western blotting or subjected to Immunoprecipitation (for MEK5 and ERK5) prior blotting using antibodies targeting proteins of interest. ERK5 siRNA was optimised and a consistent knock-down of 60% was achieved. ERK5 siRNA (100nM) transfected cells were similarly treated but for 24h and caspase-3/7 activity measured as a measure of apoptosis. Here we show that EGF-induced activation of ERK5 in PTEC is associated with increased association of MEK5 with not only ERK5 but also MEF2C. In addition, EGF inhibited staurosporine-induced apoptosis. siRNA knockdown of ERK5 significantly (P<0.001) increased apoptosis and EGF did not alter apoptosis in the presence of ERK5 siRNA. Our work provides evidence that ERK5 may mediate EGF-induced cell survival in human PTEC. We present the first demonstration of MEF2C expression in PTEC and propose that it has a role in EGF-ERK5 cell survival.