Activating mutations in receptor tyrosine kinases play a critical role in oncogenesis. Despite evidence that Met kinase is deregulated in human cancer, the role of activating mutations in cancers other than renal papillary carcinoma has not been well defined. Here we report the identification of somatic intronic mutations of Met kinase that lead to an alternatively spliced transcript in lung cancer, which encodes a deletion of the juxtamembrane domain resulting in the loss of Cbl E3-ligase binding. The mutant receptor exhibits decreased ubiquitination and delayed down-regulation correlating with elevated, distinct Met expression in primary tumors harboring the deleted receptor. As a consequence, phospho-Met and downstream mitogen-activated protein kinase activation is sustained on ligand stimulation. Cells expressing the Met deletion reveal enhanced ligand-mediated proliferation and significant in vivo tumor growth. A hepatocyte growth factor competitive Met antagonist inhibits receptor activation and proliferation in tumor cells harboring the Met deletion, suggesting the important role played by ligand-dependent Met activation and the potential for anticancer therapy. These results support a critical role for Met in lung cancer and somatic mutation-driven splicing of an oncogene that leads to a different mechanism for tyrosine kinase activation through altered receptor down-regulation in human cancer. (Cancer Res 2006; 66(1): 283-9)

Hepatocyte growth factor (HGF) binds the extracellular domain and activates the Met receptor to induce mitogenesis, morphogenesis, and motility. The extracellular domain of Met is comprised of Sema, PSI, and four IPT subdomains. We investigated the contribution of these subdomains to Met receptor dimerization. Our observations indicate that the Sema domain is necessary for dimerization in addition to HGF binding. Treatment of Met-overexpressing tumor cells with recombinant Sema in the presence or absence of HGF results in decreased Met-mediated signal transduction, cell motility, and migration, behaving in a manner similar to an antagonistic anti-Met Fab. These data suggest that the Sema domain of Met may not only represent a novel anticancer therapeutic target but also acts as a biotherapeutic itself.

Background: Therapeutic inhibition of circulating PCSK9 reduces LDL-c levels. Results: A synthetic PCSK9-binding peptide, which restores cellular LDL receptors, was identified. Conclusion: Pep2-8 is the smallest PCSK9 inhibitor with a defined inhibitory mechanism described to date and structurally mimics the EGF(A) domain of the receptor. Significance: This work demonstrates the feasibility of developing a peptide-based inhibitor of PCSK9.

Background: Two forms of PCSK9, an intact and a furin cleaved form, circulate in blood.Results: Both forms, as highly purified recombinant proteins, are able to bind to and trigger degradation of LDL receptors and elevate serum cholesterol levels.Conclusion: Furin cleavage is not associated with a loss of PCSK9 polypeptides or a significant loss of function.Significance: LDL-c levels are controlled by both forms of PCSK9.

BackgroundMaturity-onset diabetes of the young (MODY) is an early-onset, autosomal dominant form of non-insulin dependent diabetes. Genetic diagnosis of MODY can transform patient management. Earlier data on the genetic predisposition to MODY have come primarily from familial studies in populations of European origin.MethodsIn this study, we carried out a comprehensive genomic analysis of 289 individuals from India that included 152 clinically diagnosed MODY cases to identify variants in known MODY genes. Further, we have analyzed exome data to identify putative MODY relevant variants in genes previously not implicated in MODY. Functional validation of MODY relevant variants was also performed.ResultsWe found MODY 3 (HNF1A; 7.2%) to be most frequently mutated followed by MODY 12 (ABCC8; 3.3%). They together account for ~ 11% of the cases. In addition to known MODY genes, we report the identification of variants in RFX6, WFS1, AKT2, NKX6–1 that may contribute to development of MODY. Functional assessment of the NKX6–1 variants showed that they are functionally impaired.ConclusionsOur findings showed HNF1A and ABCC8 to be the most frequently mutated MODY genes in south India. Further we provide evidence for additional MODY relevant genes, such as NKX6–1, and these require further validation.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0528-6) contains supplementary material, which is available to authorized users.