Cell communication and signaling : CCS · 2026
Mindin-mediated αM-integrin endocytosis activates STAT3 to maintain keratinocyte stemness.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Dam Binita, Ajnabi Johan, Saha Tirthankar, Shrivastava Ashish, Badarinath Krithika, Hegde Akshay, Dutta Abhik, Jasoria Siddham, Kataria Sunny, Singh Ashutosh, Jamora Colin
Аннотация
BACKGROUND: Keratinocyte stem cells are essential for maintaining epidermal homeostasis and enabling efficient tissue repair. Regulation of their self-renewal and differentiation is critical, as its disruption can impair regeneration and drive pathological conditions such as chronic wounds and cancer. We previously identified the matricellular protein Mindin as a key regulator of keratinocyte stemness through its interaction with the αMβ2 (CD11b/CD18) integrin and subsequent activation of the transcription factor STAT3. However, the mechanism connecting Mindin and integrin at the cell surface to the intracellular activation of STAT3 remained undefined.
METHODS: We employ biochemical and imaging analysis along with molecular dynamics simulations to dissect Mindin-integrin-STAT3 signalling in primary mouse keratinocytes. Stemness of epidermal keratinocytes are assessed using bulk RNA sequencing, quantitative PCR, and cell-based assays.
RESULTS: Our work demonstrates that the F-Spondin domain of Mindin constitutes the minimal integrin-binding module required to initiate downstream signalling. F-Spondin binding to the integrin at the plasma membrane does not elicit the full activation state of the integrin. Instead, it promotes Src-kinase dependent endocytosis of the integrin receptor to the early endosomes. Analysis of integrin conformational dynamics reveals that the acidic environment of early endosomes is essential to achieve a signalling-competent state. This mechanism extends to pathological contexts, as we demonstrate a requirement for endocytosis in activating STAT3 signalling and preserving stem-like properties in a cancer stem cell model.
CONCLUSIONS: These findings highlight a previously unrecognized layer of spatial control in integrin signalling, confirming endosomal trafficking as a critical determinant of stem cell behaviour and offering new conceptual and therapeutic opportunities across regenerative biology and cancer.
METHODS: We employ biochemical and imaging analysis along with molecular dynamics simulations to dissect Mindin-integrin-STAT3 signalling in primary mouse keratinocytes. Stemness of epidermal keratinocytes are assessed using bulk RNA sequencing, quantitative PCR, and cell-based assays.
RESULTS: Our work demonstrates that the F-Spondin domain of Mindin constitutes the minimal integrin-binding module required to initiate downstream signalling. F-Spondin binding to the integrin at the plasma membrane does not elicit the full activation state of the integrin. Instead, it promotes Src-kinase dependent endocytosis of the integrin receptor to the early endosomes. Analysis of integrin conformational dynamics reveals that the acidic environment of early endosomes is essential to achieve a signalling-competent state. This mechanism extends to pathological contexts, as we demonstrate a requirement for endocytosis in activating STAT3 signalling and preserving stem-like properties in a cancer stem cell model.
CONCLUSIONS: These findings highlight a previously unrecognized layer of spatial control in integrin signalling, confirming endosomal trafficking as a critical determinant of stem cell behaviour and offering new conceptual and therapeutic opportunities across regenerative biology and cancer.