Abstract
The tumor suppressor Smad4/DPC4 is an essential transcription factor in the TGF-β pathway and is frequently mutated or deleted in prostate, colorectal, and pancreatic carcinomas. We recently discovered that Smad4 activity and stability are regulated by the FGF/EGF and Wnt signaling pathways through a series of MAPK and GSK3 phosphorylation sites located in its linker region. In the present study, we report that loss-of-function associated with 2 point mutations commonly found in colorectal and pancreatic cancers results from enhanced Smad4 phosphorylation by GSK3, generating a phosphodegron that leads to subsequent β-TrCP–mediated polyubiquitination and proteasomal degradation. Using chemical GSK3 inhibitors, we show that Smad4 point mutant proteins can be stabilized and TGF-β signaling restored in cancer cells harboring such mutations.
Highlights
The transforming growth factor-b (TGF-b) family of cytokines constitutes the largest group of growth factors in humans and regulates many aspects of cell behavior such as differentiation, migration, and apoptosis.[1]
Others had observed that point mutations commonly found in colorectal and pancreatic cancers enhance the interaction between Smad[4] and b-transducin repeat-containing protein (b-TrCP).[25]
Replacing Smad[4] with various mutations in a smad¡/¡ mammary cancer cell line showed that TGF-b signaling is greatly impaired by point mutations that naturally occur in cancer, and that in 2 of these cases signaling via a synthetic TGF-b reporter gene can be reactivated by inhibiting glycogen synthase kinase-3 (GSK3) activity
Summary
The transforming growth factor-b (TGF-b) family of cytokines constitutes the largest group of growth factors in humans and regulates many aspects of cell behavior such as differentiation, migration, and apoptosis.[1] The TGF-b pathway exerts potent antitumor effects and its misregulation often results in cancer progression.[2] In the canonical TGF-b signaling pathway, activated TGF-b receptors phosphorylate C-terminal serine residues of the transcription factors Smad1/5/8 for bone morphogenetic proteins (BMPs) or Smad2/3 for the TGF-b/activin branch of the pathway.[3] The transcription factor Smad[4], called deleted in pancreatic carcinoma 4 (DPC4), functions as a coSmad that binds to receptor-phosphorylated Smads (R-Smads) and is an essential downstream determinant in TGF-b signaling that was, until recently, considered a constitutive component of the pathway.[3]. Among patients undergoing surgical removal of pancreatic adenocarcinoma, survival was found to be significantly longer for patients whose tumors express Smad[4] protein.[8]
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