RIPK4 regulates cell–cell adhesion in epidermal development and homeostasis

Abstract

Epidermal development and maintenance are finely regulated events requiring a strict balance between proliferation and differentiation. Alterations in these processes give rise to human disorders such as cancer or syndromes with skin and annexes defects, known as ectodermal dysplasias (EDs). Here, we studied the functional effects of two novel receptor-interacting protein kinase 4 (RIPK4) missense mutations identified in siblings with an autosomal recessive ED with cutaneous syndactyly, palmoplantar hyperkeratosis and orofacial synechiae. Clinical overlap with distinct EDs caused by mutations in transcription factors (i.e. p63 and interferon regulatory factor 6, IRF6) or nectin adhesion molecules was noticed. Impaired activity of the RIPK4 kinase resulted both in altered epithelial differentiation and defective cell adhesion. We showed that mutant RIPK4 resulted in loss of PVRL4/nectin-4 expression in patient epidermis and primary keratinocytes, and demonstrated that PVRL4 is transcriptionally regulated by IRF6, a RIPK4 phosphorylation target. In addition, defective RIPK4 altered desmosome morphology through modulation of plakophilin-1 and desmoplakin. In conclusion, this work implicates RIPK4 kinase function in the p63-IRF6 regulatory loop that controls the proliferation/differentiation switch and cell adhesion, with implications in ectodermal development and cancer.

Receptor-interacting protein kinase 2 is associated with tumor immune infiltration, immunotherapy-related biomarkers, and affects gastric cancer cells growth in vivo

“…The upregulation of RIPK3 has been shown to increase the production of immunostimulatory cytokines in the tumor microenvironment, leading to a robust cytotoxic anti-tumor immune response 9 . Additionally, RIPK4 has been identified as an immune regulating-associated biomarker in ovarian cancer 11 , 29 , where it plays a role in regulating the growth of squamous cell carcinoma 30 and cell-cell adhesion in epidermal development and homeostasis 31 . All of the aforementioned studies have demonstrated the significant role of RIPKs genes in the regulation of immune-related diseases, such as tumors.…”