Pran K. Datta

Members of the TGF-beta superfamily exhibit various biological activities, and perturbations of their signaling are linked to certain clinical disorders including cancer. The role of TGF-beta signaling as a tumor suppressor pathway is best illustrated by the presence of inactivating mutations in genes encoding TGF-beta receptors and Smads in human carcinomas. This perspective is further supported by studies of tumor development in mouse models after modulation of receptors and Smads. TGF-beta also controls processes such as cell invasion, immune regulation, and microenvironment alterations that cancer cells may exploit to their advantage for their progression. Consequently, the output of a TGF-beta response is highly situation dependent, across different tissues, and also in cancer in general. Understanding the mechanisms of TGF-beta superfamily signaling is thus important for the development of new ways to treat various types of cancer. This review focuses on recent advances in understanding the Smad dependent TGF-beta pathway as it relates to human carcinogenesis.

Glycogen synthase kinase 3β (GSK3β) can regulate a broad range of cellular processes in a variety of cell types and tissues through its ability to phosphorylate its substrates in a cell- and time-specific manner. Although it is known that Axin and presenilin help to recruit β-catenin/Smad3 and tau protein to GSK3β, respectively, it is not clear how many of the other GSK3β substrates are recruited to it. Here, we have established the binding of GSK3β with a novel scaffold protein, STRAP, through its WD40 domains. In a new finding, we have observed that STRAP, GSK3β and Axin form a ternary complex together. We show for the first time that intracellular fragment of Notch3 (ICN3) binds with GSK3β through the ankyrin repeat domain. This binding between STRAP and GSK3β is reduced by small-molecule inhibitors of GSK3β. Further studies revealed that STRAP also binds ICN3 through the ankyrin repeat region, and this binding is enhanced in a proteasomal inhibition-dependent manner. In vivo ubiquitination studies ind...

The serine-threonine kinase receptor-associated protein (STRAP) was initially identified as a putative inhibitor of the canonical TGF-beta signaling pathway. Because the Smad-dependent TGF-beta pathway negatively regulates cellular growth, early functional studies suggested that STRAP behaves as an oncogene. Indeed, a correlation between STRAP overexpression and various cancers has been identified. With the emergence of new studies on the biological function of STRAP, it is becoming clear that STRAP regulates several distinct cellular processes and modulates multiple signaling pathways. While STRAP itself does not possess enzymatic activity, it appears that STRAP influences biological processes through associations with cellular proteins. In this review, we will describe the TGF-beta-dependent and -independent functions of STRAP and provide a context for the significance of STRAP activity in the development of cancer.

The transforming growth factor-ß (TGF-β) signaling pathway plays a pivotal role in diverse cellular processes. TGF-β switches its role from a tumor suppressor in normal or dysplastic cells to a tum...

Although Smad signalling is known to play a tumour suppressor role, it has been shown to play a prometastatic function also in breast cancer and melanoma metastasis to bone. In contrast, mutation or reduced level of Smad4 in colorectal cancer is directly correlated to poor survival and increased metastasis. However, the functional role of Smad signalling in metastasis of colorectal cancer has not been elucidated. We previously reported that overexpression of Smad7 in colon adenocarcinoma (FET) cells induces tumorigenicity by blocking TGF-β-induced growth inhibition and apoptosis. Here, we have observed that abrogation of Smad signalling by Smad7 induces liver metastasis in a splenic injection model. Polymerase chain reaction with genomic DNA from liver metastases indicates that cells expressing Smad7 migrated to the liver. Increased expression of TGF-β type II receptor in liver metastases is associated with phosphorylation and nuclear accumulation of Smad2. Immunohistochemical analyses have suggested poorly differentiated spindle cell morphology and higher cell proliferation in Smad7-induced liver metastases. Interestingly, we have observed increased expression and junctional staining of Claudin-1, Claudin-4 and E-cadherin in liver metastases. Therefore, this report demonstrates, for the first time, that blockade of TGF-β/Smad pathway in colon cancer cells induces metastasis, thus supporting an important role of Smad signalling in inhibiting colon cancer metastasis.

Members of the transforming growth factor-beta (TGF-beta) family regulate a wide range of biological processes including cell proliferation, migration, differentiation, apoptosis, and extracellular matrix deposition. Resistance to TGF-beta-mediated tumour suppressor function in human lung cancer may occur through the loss of type II receptor (TbetaRII) expression. In this study, we investigated the expression pattern of TbetaRII in human lung cancer tissues by RT-PCR and Western blot analyses. We observed downregulation of TbetaRII in 30 out of 46 NSCLC samples (65%) by semiquantitative RT-PCR. Western blot analyses with tumour lysates showed reduced expression of TbetaRII in 77% cases. We also determined the effect of TbetaRII expression in lung adenocarcinoma cell line (VMRC-LCD) that is not responsive to TGF-beta due to lack of TbetaRII expression. Stable expression of TbetaRII in these cells restored TGF-beta-mediated effects including Smad2/3 and Smad4 complex formation, TGF-beta-responsive reporter gene activation, inhibition of cell proliferation and increased apoptosis. Clones expressing TbetaRII showed reduced colony formation in soft-agarose assay and significantly reduced tumorigenicity in athymic nude mice. Therefore, these results suggest that reestablishment of TGF-beta signalling in TbetaRII null cells by stable expression of TbetaRII can reverse malignant behaviour of cells and loss of TbetaRII expression may be involved in lung tumour progression.