Mechano-regulation of proline metabolism and cancer progression by kindlin-2

Figures & data

Figure 1. Kindlin-2-mediated signaling pathways that link mechano-environment to proline synthesis, YAP/TAZ signaling and cancer progression.

The figure depicts signaling pathways through which fermitin family homolog 2 (FERMT2, best known as kindlin-2) links mechano-environment to proline synthesis and Yes-associated protein (YAP)/WW domain containing transcription regulator 1 (WWTRl, best known as TAZ) signaling. Kindlin-2 is recruited to cell-extracellular matrix (ECM) adhesions through interaction with integrins, where it promotes integrin activation, clustering, and downstream signaling. ECM stiffening promotes kindlin-2 translocation to mitochondria, where it interacts with pyrroline-5-carboxylate reductase 1(PYCR1), resulting in elevations of PYCR1 level and proline synthesis that promotes cell proliferation and collagen matrix synthesis, which further increases ECM stiffness.³ Kindlin-2-mediated regulation of proline synthesis also helps to maintain redox balance and cell survival. In addition, kindlin-2 interacts with myosin light chain kinase (MLCK) in response to ECM stiffening, which promotes myosin light chain phosphorylation and actomyosin contraction, resulting in inhibition of neural precursor cell expressed, developmentally down-regulated 4(NEED4)-like E3 ubiquitin ligase Atrophin-interacting Protein 4(AIP4)-mediated YAP/TAZ degradation and increase of YAP/TAZ expression and signaling.⁸ α-KG: α-ketoglutarate; P5C: Δ1-pyrroline-5-carboxylate; ROS: reactive oxygen species; TCA: tricarboxylic acid cycle; TEAD1: TEA domain family member 1; RHOA: Ras homolog family member A.

Guo L, Cui C, Zhang K, Wang J, Wang Y, Lu Y, Chen K, Yuan J, Xiao G, Tang B, et al. Kindlin-2 links mechano-environment to proline synthesis and tumor growth. Nat Commun. 2019;10(1):845. doi:10.1038/s41467-019-08772-3.

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Guo L, Cai T, Chen K, Wang R, Wang J, Cui C, Yuan J, Zhang K, Liu Z, Deng Y, et al. Kindlin-2 regulates mesenchymal stem cell differentiation through control of YAP1/TAZ. J Cell Biol. 2018;217(4):1431–1451. doi:10.1083/jcb.201612177.

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