Rognoni Emanuel, Ruppert Raphael, Fässler Reinhard
Max Planck Institute of Biochemistry, Martinsried 82152, Germany.
Max Planck Institute of Biochemistry, Martinsried 82152, Germany
J Cell Sci. 2016 Jan 1;129(1):17-27. doi: 10.1242/jcs.161190.
The kindlin (or fermitin) family of proteins comprises three members (kindlin-1,-2 and -3) of evolutionarily conserved focal adhesion (FA) proteins, whose best-known task is to increase integrin affinity for a ligand (also referred as integrin activation) through binding of β-integrin tails. The consequence of kindlin-mediated integrin activation and integrin-ligand binding is cell adhesion, spreading and migration, assembly of the extracellular matrix (ECM), cell survival, proliferation and differentiation. Another hallmark of kindlins is their involvement in disease. Mutations in the KINDLIN-1 (also known as FERMT1) gene cause Kindler syndrome (KS)--in which mainly skin and intestine are affected, whereas mutations in the KINDLIN-3 (also known as FERMT3) gene cause leukocyte adhesion deficiency type III (LAD III), which is characterized by impaired extravasation of blood effector cells and severe, spontaneous bleedings. Also, aberrant expression of kindlins in various forms of cancer and in tissue fibrosis has been reported. Although the malfunctioning of integrins represent a major cause leading to kindlin-associated diseases, increasing evidence also point to integrin-independent functions of kindlins that play an important role in the pathogenesis of certain disease aspects. Furthermore, isoform-specific kindlin functions have been discovered, explaining, for example, why loss of kindlins differentially affects tissue stem cell homeostasis or tumor development. This Commentary focuses on new and isoform-specific kindlin functions in different tissues and discusses their potential role in disease development and progression.
亲联蛋白（或费米汀）家族蛋白由进化上保守的粘着斑（FA）蛋白的三个成员（亲联蛋白-1、-2和-3）组成，其最广为人知的任务是通过结合β整合素尾部来增加整合素对配体的亲和力（也称为整合素激活）。亲联蛋白介导的整合素激活以及整合素-配体结合的结果是细胞粘附、铺展和迁移、细胞外基质（ECM）组装、细胞存活、增殖和分化。亲联蛋白的另一个特征是它们与疾病有关。KINDLIN-1（也称为FERMT1）基因突变会导致Kindler综合征（KS）——主要影响皮肤和肠道，而KINDLIN-3（也称为FERMT3）基因突变会导致III型白细胞粘附缺陷（LAD III），其特征是血液效应细胞渗出受损和严重的自发性出血。此外，还报道了亲联蛋白在各种癌症和组织纤维化中的异常表达。尽管整合素功能异常是导致亲联蛋白相关疾病的主要原因，但越来越多的证据也表明亲联蛋白具有不依赖整合素的功能，这些功能在某些疾病方面的发病机制中起着重要作用。此外，还发现了亚型特异性的亲联蛋白功能，例如解释了为什么亲联蛋白的缺失对组织干细胞稳态或肿瘤发展有不同的影响。本述评重点关注不同组织中亲联蛋白的新功能和亚型特异性功能，并讨论它们在疾病发生和发展中的潜在作用。
