Transforming growth factors β (TGF‐βs) are multifunctional cytokines, which are secreted in latent forms in large latent TGF‐β complexes (LL‐TGF‐β) with subsequent deposition to the extracellular matrix (ECM). While a variety of mechanisms capable of activating latent TGF‐β in vitro have been described, the physiological conditions, which promote the activation of TGF‐β in vivo are poorly understood. Mink lung epithelial cells (Mv1Lu) are a widely used model for evaluation of the effects of exogenous TGF‐β both in transcriptional and growth inhibitor assays. We find here that apoptosis of Mv1Lu cells, induced either by staurosporine or serum deprivation, is accompanied by proteolytic processing of LL‐TGF‐β and the activation of endogenous TGF‐β. Activation of TGF‐β preceded caspase‐3 activation and was almost completely suppressed by the serine protease inhibitor, AEBSF. Both exogenous and endogenously activated TGF‐βs were able to enhance the apoptotic response of Mv1Lu cells leading to potentiation of cell death. Potentiation of cell death by activated TGF‐β was associated with downregulation of Akt and p38 MAPK, which were both activated at the initial stages of Mv1Lu apoptosis and were suppressed by exogenous TGF‐β. Pharmacological interruption of either phosphoinositide‐3‐kinase (PI‐3K)/Akt or p38 MAPK signaling by the specific inhibitors mimicked the effect of TGF‐β leading to potentiation of cell death. Current results suggest that proteolytic activation of endogenous TGF‐β is a component of the apoptotic response, capable of modulating the death of Mv1Lu cells by inhibition of both PI‐3K/Akt and p38 MAPK‐dependent survival pathways. J. Cell. Physiol. 207: 445–453, 2006. © 2006 Wiley‐Liss, Inc.