Systemic analysis of TGFbeta proteomics revealed involvement of Plag1/CNK1/RASSF1A/Src network in TGFbeta1-dependent activation of Erk1/2 and cell proliferation.
Transforming growth factor-beta (TGFbeta) is a key regulator of cell proliferation, death, migration, and differentiation. To explore mechanisms of TGFbeta 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 TGFbeta1. We found that TGFbeta1 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 TGFbeta1 signaling. Network analysis demonstrated importance of a Plag1/CNK1/RASSF1A/Src-dependent prozone effect, as a systemic feature which is crucial for TGFbeta1-dependent activation of Erk1/2 and regulation of cell proliferation. We showed that the balance between Plag1, CNK1, RASSF1A and Src defined whether TGFbeta1 will stimulate, inhibit or will have no effect on a long-term activation of Erk1/2 and subsequent TGFbeta1 inhibitory or stimulatory effect on cell proliferation. This is the first demonstration of importance of systemic features for incorporation of Erk1/2 activation into TGFbeta1 signaling.
Bhaskaran
Nimesh
N
Department of Oncology-Pathology, Karolinska Biomics Center, Karolinska Institute, Karolinska University Hospital, Solna, Stockholm, Sweden.
Souchelnytskyi
Serhiy
S
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000502:physiology; D004789:Enzyme Activation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics; D015398:Signal Transduction; D049490:Systems Biology; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology; D019061:src-Family Kinases / Q000502:physiology
C500833:CNKSR1 protein, human; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C104382:PLAG1 protein, human; D020543:Proteome; C411762:RASSF1 protein, human; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins; D019061:src-Family Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3