Disease relevance of PRKCSH

• In light of the focal nature of liver cysts in ADPLD, the apparent loss-of-function mutations in PRKCSH, and the two-hit mechanism operational in dominant polycystic kidney disease, ADPLD may also occur by a two-hit mechanism [1].
• A 3-Mb region for the familial hemiplegic migraine locus on 19p13.1-p13.2: exclusion of PRKCSH as a candidate gene. Dutch Migraine Genetic Research Group [2].
• We purified the 80K protein from human squamous carcinoma Ca9-22 cells and fractionated it into two distinct molecular species, designated the 80K-L and 80K-H proteins [3].
• We now report that the protein 80K-H, a substrate for PKC, appears to be part of this mechanism and that it is increased in breast cancer and localizes to the nucleus as part of the mechanism [4].

High impact information on PRKCSH

• Mutations in PRKCSH, encoding the beta-subunit of glucosidase II, an N-linked glycan-processing enzyme in the endoplasmic reticulum (ER), cause autosomal dominant polycystic liver disease [5].
• These findings establish germline mutations in PRKCSH as the probable cause of PCLD [6].
• The protein encoded by PRKCSH, here named hepatocystin, is predicted to localize to the endoplasmic reticulum [6].
• We found sequence variations in a known gene, PRKCSH, that were not observed in control individuals, that segregated with the disease haplotype, and that were predicted to be chain-terminating mutations [1].
• Immune IgG raised to recombinant OST-48 and 80K-H inhibited binding of AGE-bovine serum albumin to cell membranes in a dose-dependent manner [7].

Biological context of PRKCSH

• Germline mutations in PRKCSH are associated with autosomal dominant polycystic liver disease [6].
• The PRKCSH gene encodes hepatocystin, a protein that moderates glycosylation and fibroblast growth factor receptor signaling [8].
• Since PRKCSH is involved in neuronal signal transduction, it was considered to be an FHM candidate gene [2].
• Most of the interval was completely covered by YAC and cosmid contigs; the physical map yielded approximately 3 Mb encompassing several genes including the protein kinase substrate 80K-H (PRKCSH) gene [2].
• Two patients (11%) from group A had missense mutations (1 PRKCSH and 1 SEC63) [9].

Anatomical context of PRKCSH

• Immunostaining and flow cytometry demonstrated the surface expression of OST-48 and 80K-H on numerous cell types and tissues, including mononuclear, endothelial, renal, and brain neuronal and glial cells [7].
• Vacuolar system-associated protein-60: a protein characterized from bovine granulosa and luteal cells that is associated with intracellular vesicles and related to human 80K-H and murine beta-glucosidase II [10].
• Notably, 80K-H immunostaining was largely limited to the epithelial cells of the mammary ducts [4].
• We observed that FGF-1 treatment of MCF-7 cells stimulated translocation of 80K-H protein to the cell nucleus, as demonstrated by subcellular fractionation studies [4].
• Immunoprecipitates of endogenous PKCzeta from Cho cells, 3T3-L1 adipocytes or L6 myotubes contained endogenous 80K-H, demonstrating a physiological interaction [11].

Associations of PRKCSH with chemical compounds

• Microsequencing of p90 resolved on two-dimensional polyacrylamide gel electrophoresis indicated an N-terminal amino acid sequence which corresponded to a protein previously named as 80K-H [12].
• The amino acid sequences of the NH2-terminal region and cyanogen bromide-cleaved fragments of the 80K-H protein were determined and a corresponding oligonucleotide sequence was synthesized [3].
• AGE-R2 mRNA levels correlated with sAGE levels (r = .61, p < .05), and with creatinine clearance (r = -.63, p < .05) [13].

Physical interactions of PRKCSH

• Activated FGFR3 predominantly interacts with GRB2.Sos in complex with a previously identified 90-kDa protein and designated protein 80K-H [14].

Other interactions of PRKCSH

• In 2 Finnish families with dominantly inherited PCLD, and in 62 of 65 sporadic cases with multiple simple liver cysts, we failed to demonstrate any PRKCSH mutation [15].
• We report here a family (a mother and her daughter) with a severe form of ADPLD not associated with ADPKD produced by a novel missense protein kinase C substrate 80K-H (PRKCSH) mutation (R281W) [16].
• In total we found that eight patients with multiple liver cysts (16%) had PRKCSH (5) or SEC63 (3) mutations [9].
• Subsequently, we studied the effects of FGF-1 on 80K-H in cultured human mammary carcinoma epithelial cells in order to establish a more direct relationship between these two molecules [4].
• 80K-H phosphoprotein is involved in FGFR3 signal transduction to MAP kinase, and may be involved in AGE-receptor signal transduction [17].

Analytical, diagnostic and therapeutic context of PRKCSH

• A phosporylation assay in combination with AGE-R2 immunoprecipitation demonstrated that this component of the receptor complex is phosphorylated by acute exposure to AGE-BSA [18].

References