Rabbit Anti-Human TNIK Polyclonal antibody

Intellectual disability (ID) is one of the most common disabilities and, although many genes have been implicated in its etiology, the genetic heterogeneity of ID continues to expand. The purpose of the study was to describe a novel autosomal recessive non-syndromic ID locus. Autozygome and linkage analysis, and exome sequencing followed by RNA and protein analysis of the candidate disease gene were performed. We describe two multiplex consanguineous families with non-syndromic ID phenotype, which maps to a critical linkage locus on 3q26. Exome sequencing of the index in each family revealed the same homozygous truncating mutation in TNIK that results in complete loss of the protein. TNIK is a kinase with a well-established role in dendrite development and synaptic transmission. The phenotype we observe in human patients who lack TNIK is consistent with the previously published Tnik (-/-) phenotype in the murine model. Our data strongly implicate TNIK deficiency in the causation of ID in humans.

Wnt signalling maintains the undifferentiated state of intestinal crypt/progenitor cells through the TCF4/beta-catenin-activating transcriptional complex. In colorectal cancer, activating mutations in Wnt pathway components lead to inappropriate activation of the TCF4/beta-catenin transcriptional programme and tumourigenesis. The mechanisms by which TCF4/beta-catenin activate key target genes are not well understood. Using a proteomics approach, we identified Tnik, a member of the germinal centre kinase family as a Tcf4 interactor in the proliferative crypts of mouse small intestine. Tnik is recruited to promoters of Wnt target genes in mouse crypts and in Ls174T colorectal cancer cells in a beta-catenin-dependent manner. Depletion of TNIK and expression of TNIK kinase mutants abrogated TCF-LEF transcription, highlighting the essential function of the kinase activity in Wnt target gene activation. In vitro binding and kinase assays show that TNIK directly binds both TCF4 and beta-catenin and phosphorylates TCF4. siRNA depletion of TNIK followed by expression array analysis showed that TNIK is an essential, specific activator of Wnt transcriptional programme. This kinase may present an attractive candidate for drug targeting in colorectal cancer. The EMBO Journal (2009) 28, 3329-3340. doi: 10.1038/emboj.2009.285; Published online 8 October 2009