Systemic analysis of TGFβ proteomics revealed involvement of Plag1/CNK1/RASSF1A/Src network in TGFβ1-dependent activation of Erk1/2 and cell proliferation

Transforming growth factor-beta (TGF beta) is a key regulator of cell proliferation, death, migration, and differentiation. To explore mechanisms of TGF beta action, we performed systemic analysis of functional dependencies between 153 proteins which changed their expression and synthesis upon treatment of human breast epithelial cells with TGF beta 1. We found that TGF beta 1 initiated signaling via a scale-free network of proteins which affect primary cellular metabolism, stress response, signal transduction, transport, transcription, cytoskeleton, and cell death. Multiple inputs into each functional domain were observed, emphasizing robustness of TGF beta 1 signaling. Network analysis demonstrated importance of a Plag1/CNK1/RASSF1A/Src-dependent prozone effect, as a systemic feature which is crucial for TGF beta 1-dependent activation of Erk1/2 and regulation of cell proliferation. We showed that the balance between Plag1, CNK1, RASSF1A and Src defined whether TGF beta 1 will stimulate, inhibit or will have no effect on a long-term activation of Erk1/2 and subsequent TGF beta 1 inhibitory or stimulatory effect on cell proliferation. This is the first demonstration of importance of systemic features for incorporation of Erk1/2 activation into TGF beta 1 signaling.