Negative regulation of TGFβ signaling by the kinase LKB1 and the scaffolding protein LIP1.
Signal transduction by the Smad pathway elicits critical biological responses to many extracellular polypeptide factors, including TGFβ and bone morphogenetic protein. Regulation of Smad signaling imparts several cytoplasmic and nuclear mechanisms, some of which entail protein phosphorylation. Previous work established a protein complex between Smad4 and the scaffolding protein LKB1-interacting protein 1 (LIP1). LKB1 is a well studied tumor suppressor kinase that regulates cell growth and polarity. Here, we analyzed the LKB1-LIP1 and the Smad4-LIP1 protein complexes and found that LIP1 can self-oligomerize. We further demonstrate that LKB1 is capable of phosphorylating Smad4 on Thr(77) of its DNA-binding domain. LKB1 inhibits Smad4 from binding to either TGFβ- or bone morphogenetic protein-specific promoter sequences, which correlates with the negative regulatory effect LKB1 exerts on Smad4-dependent transcription. Accordingly, LKB1 negatively regulates TGFβ gene responses and epithelial-mesenchymal transition. Thus, LKB1 and LIP1 provide negative control of TGFβ signaling.
Morén
Anita
A
Ludwig Institute for Cancer Research, Uppsala University, Box 595, Biomedical Center, Uppsala University, SE-751 24 Uppsala, Sweden.
Raja
Erna
E
Heldin
Carl-Henrik
CH
Moustakas
Aristidis
A
D000091162:AMP-Activated Protein Kinase Kinases; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D015398:Signal Transduction; D051901:Smad4 Protein / Q000737:chemistry / Q000378:metabolism; D013912:Threonine / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; C491653:STK11IP protein, human; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D013912:Threonine; D004247:DNA; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases