Plow Edward F, Pluskota Elzbieta, Bialkowska Katarzyna
Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH, USA 44139.
J Breast Cancer Res. 2021;1(2):20-29.
Kindlin-1 (K1, FERMT1), Kindlin-2 (K2, FERMT2), and Kindlin-3 (K3, FERMT3) are the three members of the kindlin family of adapter proteins found in mammals. One or more kindlins are found in most cell types, K1 primarily in epithelial cells, K3 in primarily hematopoietic cells and also endothelial cells, and K2 is very broadly distributed. The kindlins consist primarily of a 4.1-erzin-radixin-moiesin (FERM) domain, which is transected by a lipid-binding plextrin-homology (PH) domain. Deficiencies of each kindlin in mice and/ or humans have profound pathogenic consequences. The most well-established function of kindlins depends on their ability to participate in the activat integrin adhesion receptors. This function depends on the binding of each kindlin to the beta subunit of integrins where it cooperates with talin to enhance avidity of interactions with cognate extracellular matrix ligands. Deficiencies of many different integrins are lethal, are critical for normal development of mammary tissue, and excessive expression and/or activation of certain integrins are associated with progression and metastasis of breast cancer. However, via its interaction with many other intracellular proteins, kindlins can influence numerous cellular responses. Changes in expression of each of the three kindlins have been reported in association with breast cancer, with several studies indicating that kindlins are among the most upregulated genes in breast cancer. The association of abnormal functions of K2 with breast cancer is particularly extensive with many reports indicating that it is a major driver of breast cancer via its promotion of cancer cell proliferation, survival, adhesion, migration, invasion, the epithelial-to-mesenchymal transition and its influence on macrophage recruitment and phenotype. These associations suggest that the kindlins and their functions represent an intriguing therapeutic target for exploration of breast cancer therapy.
黏着斑蛋白-1（K1，FERMT1）、黏着斑蛋白-2（K2，FERMT2）和黏着斑蛋白-3（K3，FERMT3）是在哺乳动物中发现的衔接蛋白家族黏着斑蛋白家族的三个成员。大多数细胞类型中都发现有一个或多个黏着斑蛋白，K1主要存在于上皮细胞中，K3主要存在于造血细胞以及内皮细胞中，而K2分布非常广泛。黏着斑蛋白主要由一个4.1-埃兹蛋白-根蛋白-膜突蛋白（FERM）结构域组成，该结构域被一个脂质结合的富脯氨酸同源（PH）结构域横切。小鼠和/或人类中每种黏着斑蛋白的缺陷都有深远的致病后果。黏着斑蛋白最明确的功能取决于它们参与激活整合素黏附受体的能力。该功能取决于每种黏着斑蛋白与整合素β亚基的结合，在那里它与踝蛋白协同作用，增强与同源细胞外基质配体相互作用的亲和力。许多不同整合素的缺陷是致命的，对乳腺组织的正常发育至关重要，某些整合素的过度表达和/或激活与乳腺癌的进展和转移有关。然而，通过与许多其他细胞内蛋白的相互作用，黏着斑蛋白可以影响众多细胞反应。已有报道称，三种黏着斑蛋白各自的表达变化与乳腺癌有关，多项研究表明黏着斑蛋白是乳腺癌中上调最为明显的基因之一。K2功能异常与乳腺癌的关联尤为广泛，许多报道表明它是乳腺癌的主要驱动因素，通过促进癌细胞增殖、存活、黏附、迁移、侵袭、上皮-间质转化以及对巨噬细胞募集和表型的影响。这些关联表明，黏着斑蛋白及其功能是探索乳腺癌治疗的一个有趣的治疗靶点。
