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Results for “Critical Pathways”

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At least 271 records · Page 15Linked to original sources
PubMed2002

Wnt/beta-catenin/tcf signaling: a critical pathway in gastrointestinal tumorigenesis.

Cancers of the gastrointestinal tract, including the liver, bile ducts, and pancreas, constitute the largest group of malignant tumors. Colorectal cancer is one of the most common neoplastic diseases in Western countries and one of the leading causes of cancer-related deaths. Inactivation of the adenomatous polyposis coli (APC) tumor-suppressor gene during early adenoma formation is thought to be the first genetic event in the process of colorectal carcinogenesis followed by mutations in oncogenes like K-Ras and tumor-suppressor genes like p53. Identification of the interaction of APC with the proto-oncogene beta-catenin has linked colorectal carcinogenesis to the Wnt-signal transduction pathway. The main function of APC is thought to be the regulation of free beta-catenin in concert with the glycogen synthase kinase 3beta (GSK-3beta) and Axin proteins. Loss of APC function, inactivation of Axin or activating beta-catenin mutations result in the cellular accumulation of beta-catenin. Upon translocation to the nucleus beta-catenin serves as an activator of T-cell factor (Tcf)-dependent transcription leading to an increased expression of several specific target genes including c-Myc, cyclin D1, MMP-7, and ITF-2. While APC mutations are almost exclusively found in colorectal cancers, deregulation of Wnt/beta-catenin/Tcf signaling is also common in other gastrointestinal and extra-gastrointestinal human cancers. In a fraction of hepatocellular carcinomas the Wnt pathway is deregulated by inactivation of Axin or stabilizing mutations of beta-catenin. The majority of hepatoblastomas and a group of gastric cancers also carry beta-catenin mutations. Clearly, this pathway harbors great potential for future applications in cancer diagnostics, staging, and therapy.

Colorectal Neoplasms↗
PubMed2026

A novel G13-RAPGEF2-RAP1 signaling pathway critical for platelet adhesion and aggregation.

Hemostasis and thrombosis are strongly dependent on the unique ability of platelets to rapidly activate integrin receptors and to firmly adhere to sites of injury under shear stress conditions. Central to integrin activation is the small GTPase RAP1, which itself is activated by guanine nucleotide exchange factors (GEFs). CalDAG-GEFI (RASGRP2) is the highest expressed and functionally dominant platelet RAP-GEF. However, a genome-wide association study also suggested a significant role for RAPGEF2 (PDZ-GEFI), a low-expressed RAP-GEF, in human platelet aggregation. Here, we used mice deficient in RAPGEF2 (megakaryocyte-specific, Rapgef2mKO), CalDAG-GEFI (Caldaggef1-/-), or both RAPGEF2 and CalDAG-GEFI (DKO) to characterize the contribution of RAPGEF2 signaling to platelet function, hemostasis, and thrombosis. RAPGEF2 protein was detected in murine and human platelets. Compared with control or Caldaggef1-/- platelets, both RAP1 activation and integrin αIIbβ3-mediated aggregation were significantly diminished in DKO platelets. When compared with controls, Rapgef2mKO platelets exhibited reduced integrin activation, a more reversible aggregation response, and impaired adhesion under conditions of shear stress ex vivo and in vivo. Mechanistic studies strongly suggest that RAPGEF2 operates downstream of receptors coupled to the heterotrimeric G protein G13 (GNA13), such as αIIbβ3 and the thromboxane receptor. Together, our studies provide genetic evidence that RAPGEF2 in platelets operates downstream of G13 as an important regulator of RAP1 signaling and integrin activation, especially under conditions of elevated shear stress. These findings markedly improve our understanding of G protein signaling and integrin function in platelets, with potential implications for the development of improved platelet-targeted therapies for cardiovascular disease.

Animals↗
PubMed1994

Critical pathways.

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Clinical Protocols↗