Phospho-regulated tethering of focal adhesion kinase to vinculin links force transduction to focal adhesion signaling

Cell Communication and Signaling, Год журнала: 2025, Номер 23(1)

Опубликована: Апрель 21, 2025

Abstract Focal Adhesion Kinase (FAK) is a key signaling molecule in focal adhesions (FAs) orchestrating the formation, maturation and turnover of FA complex. A controlled lifecycle essential for various cellular processes requiring mesenchymal cell migration harnessed by advanced cancers to initiate cancer invasion metastasis. The mechanical force transmitted from actin stress fibers FAs via specialized transduction components FAs. These forces are known activate signaling, suggesting communication between components, yet how this occurs mechanistically unknown. Here we demonstrate that paxillin can act as an adaptor protein connect FAK with component vinculin. Our data show connection forms inefficient basal state but suggest Y925 phosphorylation mechanism optimal formation FAK:paxillin:vinculin linkage. This achieved switching binding LD2 motif vinculin while keeping LD4 tethered FAK. We further provide first high-resolution crystal structure bound tail domain, which importantly shows simultaneously link actin. therefore ensures intact role apparatus With data, all interactions transmitting tether structurally defined atomic model activation. In summary, propose phospho-regulated allowing induced activation signaling.

Язык: Английский

The integrin adhesome and control of anti-tumour immunity

Biochemical Society Transactions, Год журнала: 2024, Номер unknown

Опубликована: Дек. 6, 2024

It is widely regarded that the anti-tumour immune response drives clearance of tumours and leads to prolonged survival in patients. However, are adept at reprogramming surrounding microenvironment an immunosuppressive milieu prevent successful directed killing. Adhesion cells extracellular matrix essential for regulating cellular processes such as survival, proliferation migration. This adhesion largely conducted via integrins their related intracellular signalling networks. proteins focal kinase (FAK) expressed both tumour microenvironment, often dysregulated cancers. Recent work has demonstrated contributing regulation within tumours, could provide a new avenue target combination with immunotherapies. Here, we overview effort being made elucidate roles play modulating responses variety cancer settings. In particular focus on multifaceted role FAK microenvironment. Finally, summarise data clinical trials, where targeting exploited prime create potent when combined

Язык: Английский

Inducible FAK Deletion but not FAK Inhibition in Endothelial Cells Activates p53 to Suppress Tumor Growth in PYK2-null Mice

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 6, 2024

Abstract Focal adhesion kinase (FAK) functions as a signaling and scaffolding protein within endothelial cells (ECs) impacting blood vessel function tumor growth. Interpretations of EC FAK-null phenotypes are complicated by related PYK2 (protein tyrosine 2) expression, to test this, we created -/- FAK fl/fl mice with tamoxifen-inducible EC-specific Cre recombinase expression. At 11 weeks age, inactivation resulted in increased heart lung mass vascular leakage only on background. Surprisingly, ∼90% survived 75 age. Syngeneic melanoma, breast, or carcinoma tumors did not grow mice, but grew normally lacking Cre. This inhibitory phenotype was associated abortive sprouting, enhanced p53 suppressor p21CIP1 (cyclin-dependent inhibitor 1) alterations serum cytokine levels. To discern the role versus activity ECs, generated defective (FAK K454R, KD) fl/KD fl/WT (WT, wildtype) mice. Hemizygous -/KD expression supported primary growth metastasis, implicating dissemination. In vitro , hemizygous either WT KD suppressed levels cell death observed ECs. Combined knockdown also PARP1 (poly ADP-ribose polymerase p53-associated manner anchorage-independent Together, these results underscore linkage between loss activation Impact Statement PYK2-null combined cell-specific transgenic mouse models show that limits spread genetic chemical degradation preventing FAK-PYK2 may be an approach induce anti-tumor response.

Язык: Английский