Disease relevance of DYRK1B

• The Mirk-binding protein DCoH has been shown to be selectively expressed in colon carcinomas but not in normal tissue [1].
• Mirk may mediate tumor cell survival in mitogen-poor environments or early in colon cancer development before many autocrine growth factors have been induced [2].
• This survival function is maintained in rhabdomyosarcoma, where Mirk may be a novel therapeutic target [3].
• Thus, Mirk is a survival factor for pancreatic ductal adenocarcinoma [4].
• Mirk was an active kinase in each pancreatic cancer cell line where it was detected [4].

High impact information on DYRK1B

• Mirk is a stress-activated kinase that mediates expression of contractile proteins in differentiating myoblasts, but Mirk is not essential for muscle formation in the embryo [3].
• Mirk was detected in each rhabdomyosarcoma cell line examined [3].
• The function of the serine/threonine kinase Mirk was investigated in this cancer [3].
• The kinase Mirk/Dyrk1B mediates cell survival in pancreatic ductal adenocarcinoma [4].
• It is likely that Mirk also facilitates survival of satellite cell-derived rhabdomyoblasts in regenerating skeletal muscle and aids their differentiation [3].

Chemical compound and disease context of DYRK1B

• Minibrain-related kinase (Mirk)/Dyrk1B is an arginine-directed serine/threonine kinase that is active in skeletal muscle development but is also expressed in various carcinomas [5].
• The serine/threonine kinase Mirk/Dyrk1B has been shown to be antiapoptotic in rhabdomyosarcomas [4].

Biological context of DYRK1B

• The human DYRK1B gene was mapped to chromosome 19 (19q12-13.11) by radiation hybrid analysis [6].
• The amino acid sequences of DYRK1A and DYRK1B are 84% identical in the N-terminus and the catalytic domain but show no extended sequence similarity in the C-terminal region [6].
• Overexpression of DYRK1A or the related kinase, DYRK1B, resulted in an enhanced phosphorylation of Thr434 in endogenous SF3b1 in COS-7 cells [7].
• DCoHm (dimerization cofactor of hepatocyte nuclear factor 1alpha ( HNF1alpha) from muscle), a novel gene of the DCoH family with 78% amino acid identity to DCoH, was identified as a Mirk-binding protein by yeast two-hybrid analysis and cloned [1].
• A comparison of the mouse and human Dyrk1b genomic and cDNA sequences defined the alternative splicing events that produce the variants of DYRK1B [8].

Anatomical context of DYRK1B

• A green fluorescent protein (GFP) fusion protein of DYRK1B was found mainly in the nucleus of transfected COS-7 cells [6].
• Here we describe a highly similar homolog, DYRK1B, which is, in contrast to DYRK1A, predominately expressed in muscle and testis [6].
• Colon carcinoma cell lines stably overexpressing Mirk proliferated in serum-free medium, but the mechanism of Mirk action is unknown [1].
• Mirk/Dyrk1B is an arginine-directed serine/threonine protein kinase that is expressed at low levels in most normal tissues but at elevated levels in many tumor cell lines and in normal skeletal muscle [1].
• Involvement of GSK-3beta and DYRK1B in Differentiation-inducing Factor-3-induced Phosphorylation of Cyclin D1 in HeLa Cells [9].

Associations of DYRK1B with chemical compounds

• Mirk co-immunoprecipitated with DCoHm and bound to DCoHm in glutathione S-transferase pull-down assays [1].
• These results suggest that DIF-3 induces degradation of cyclin D1 through the GSK-3beta- and DYRK1B-mediated threonine phosphorylation in HeLa cells [9].
• DYRK1B-p65 lacked kinase activity in vitro and did not contain phosphotyrosine [8].
• Disruption of cadherin ligation by EGTA or prevention of cadherin ligation by maintenance of cells at subconfluent density blocked activation of Mirk [10].
• Mirk/dyrk1B is an arginine-directed protein kinase, which functions as a transcriptional activator and mediates serum-free growth of colon carcinoma cells by an unknown mechanism [11].

Regulatory relationships of DYRK1B

• In each of three colon carcinoma cell lines, mirk levels were increased 20-fold when erk activation was blocked by the MEK inhibitor PD98059 in serum-free medium [2].
• RanBPM inhibited the kinase activity of Mirk/Dyrk1B and Dyrk1A [5].

Other interactions of DYRK1B

• Mirk is a mitogen-activated protein kinase substrate but is down-regulated by activated extracellular signal-regulated kinases (erks) in vivo [2].
• The Mirk-RanBPM association was confirmed by glutathione S-transferase pull-down assays, co-immunoprecipitation studies, and in vivo cross-linking [5].
• Size fractionation by fast protein liquid chromatography on Superdex 200 demonstrated that Mirk is not found as a monomer in vivo, but is found within 150-700 kDa subnuclear complexes, which co-migrate with the nuclear body scaffolding protein PML [12].
• Further, we found that not only GSK-3beta but also DYRK1B modulates cyclin D1 subcellular localization by the phosphorylation of Thr(288) [9].
• The effect of DIF-3 on DYRK1B activity was examined and we found that DIF-3 also activated this kinase [9].

Analytical, diagnostic and therapeutic context of DYRK1B

• Mirk protein was detected by immunohistochemistry in 25 of 28 cases (89%) of pancreatic ductal adenocarcinoma, with elevated expression in 11 cases (39%) [4].

References