ARHGAP42 encodes Rho GTPase activating protein 42 that belongs to a member of the GTPase Regulator Associated with Focal Adhesion Kinase (GRAF) family. ARHGAP42 is involved in blood pressure control by regulating vascular tone. Despite these findings, disorders of human variants in the coding part of ARHGAP42 have not been reported. Here, we describe an 8-year-old girl with childhood interstitial lung disease (chILD), systemic hypertension, and immunological findings who carries a homozygous stop-gain variant (c.469G>T, p.(Glu157Ter)) in the ARHGAP42 gene. The family history is notable for both parents with hypertension. Histopathological examination of the proband lung biopsy showed increased mural smooth muscle in small airways and alveolar septa, and concentric medial hypertrophy in pulmonary arteries. ARHGAP42 stop-gain variant in the proband leads to exon 5 skipping, and reduced ARHGAP42 levels, which was associated with enhanced RhoA and Cdc42 expression. This is the first report linking a homozygous stop-gain variant in ARHGAP42 with a chILD disorder, systemic hypertension, and immunological findings in human patient. Evidence of smooth muscle hypertrophy on lung biopsy and an increase in RhoA/ROCK signaling in patient cells suggests the potential mechanistic link between ARHGAP42 deficiency and the development of chILD disorder.

• MeSH
• dítě MeSH
• homozygot MeSH
• hypertenze genetika   MeSH
• intersticiální plicní nemoci genetika   patologie   MeSH
• leukocytóza genetika   imunologie   MeSH
• lidé MeSH
• lymfocytóza genetika   imunologie   MeSH
• myši MeSH
• proteiny aktivující GTPasu genetika   MeSH
• rhoA protein vázající GTP genetika   metabolismus   MeSH
• rodokmen MeSH
• sekvenování exomu MeSH
• zvířata MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• ARHGAP42 protein, human MeSH Prohlížeč
• Graf3 protein, mouse MeSH Prohlížeč
• proteiny aktivující GTPasu MeSH
• rhoA protein vázající GTP MeSH
• RHOA protein, human MeSH Prohlížeč

Protein kinase N3 (PKN3) is a serine/threonine kinase implicated in tumor progression of multiple cancer types, however, its substrates and effector proteins still remain largely understudied. In the present work we aimed to identify novel PKN3 substrates in a phosphoproteomic screen using analog sensitive PKN3. Among the identified putative substrates we selected ARHGAP18, a protein from RhoGAP family, for validation of the screen and further study. We confirmed that PKN3 can phosphorylate ARHGAP18 in vitro and we also characterized the interaction of the two proteins, which is mediated via the N-terminal part of ARHGAP18. We present strong evidence that PKN3-ARHGAP18 interaction is increased upon ARHGAP18 phosphorylation and that the phosphorylation of ARHGAP18 by PKN3 enhances its GAP domain activity and contributes to negative regulation of active RhoA. Taken together, we identified new set of potential PKN3 substrates and revealed a new negative feedback regulatory mechanism of Rho signaling mediated by PKN3-induced ARHGAP18 activation.

• Klíčová slova
• ARHGAP18, PKN3, Rho-GTP, phosphoproteomic screen, phosphorylation,
• MeSH
• fosforylace MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• proteinkinasa C genetika   metabolismus   MeSH
• proteiny aktivující GTPasu metabolismus   MeSH
• proteomika metody   MeSH
• sekvence aminokyselin MeSH
• signální transdukce MeSH
• substrátová specifita MeSH
• vazba proteinů MeSH
• zpětná vazba fyziologická MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ARHGAP18 protein, human MeSH Prohlížeč
• protein kinase N MeSH Prohlížeč
• proteinkinasa C MeSH
• proteiny aktivující GTPasu MeSH