Cutaneous manifestations in Costello syndrome: HRAS p.Gly12Ser affects RIN1-mediated integrin trafficking in immortalized epidermal keratinocytes. Issue 2 (18th August 2022)

• Record Type: Journal Article
• Authors: Nauth, Theresa; Bazgir, Farhad; Voß, Hannah; Brandenstein, Laura I; Mosaddeghzadeh, Niloufar; Rickassel, Verena; Deden, Sophia; Gorzelanny, Christian; Schlüter, Hartmut; Ahmadian, Mohammad R; Rosenberger, Georg
• Is Part Of: Human molecular genetics. Volume 32:Issue 2(2023)
• Page Start: 304
• Page End: 318
• Publication Date: 2022-08-18
• Subjects: Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddac188
• Languages: English
• ISSNs: 0964-6906

Abstract

Abstract: Heterozygous germline missense variants in the HRAS gene underlie Costello syndrome (CS). The molecular basis for cutaneous manifestations in CS is largely unknown. We used an immortalized human cell line, HaCaT keratinocytes, stably expressing wild-type or CS-associated (p.Gly12Ser) HRAS and defined RIN1 as quantitatively most prominent, high-affinity effector of active HRAS in these cells. As an exchange factor for RAB5 GTPases, RIN1 is involved in endosomal sorting of cell-adhesion integrins. RIN1-dependent RAB5A activation was strongly increased by HRAS Gly12Ser, and HRAS-RIN1-ABL1/2 signaling was induced in HRAS WT - and HRAS Gly12Ser -expressing cells. Along with that, HRAS Gly12Ser expression decreased total integrin levels and enriched β1 integrin in RAB5- and EEA1-positive early endosomes. The intracellular level of active β1 integrin was increased in HRAS Gly12Ser HaCaT keratinocytes due to impaired recycling, whereas RIN1 disruption raised β1 integrin cell surface distribution. HRAS Gly12Ser induced co-localization of β1 integrin with SNX17 and RAB7 in early/sorting and late endosomes, respectively. Thus, by retaining β1 integrin in intracellular endosomal compartments, HRAS-RIN1 signaling affects the subcellular availability of β1 integrin. This may interfere with integrin-dependent processes as we detected for HRAS Gly12Ser cells spreading on fibronectin. We conclude that dysregulation of receptor trafficking and integrin-dependent processes such as cell adhesion are relevant in the pathobiology of CS.