Kindlins as modulators of breast cancer progression.

Journal of breast cancer research Pub Date : 2021-01-01
Edward F Plow, Elzbieta Pluskota, Katarzyna Bialkowska
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Abstract

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.

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作为乳腺癌进展调节剂的 Kindlins。
Kindlin-1(K1,FERMT1)、Kindlin-2(K2,FERMT2)和Kindlin-3(K3,FERMT3)是哺乳动物中发现的适配蛋白kindlin家族的三个成员。大多数细胞类型中都存在一种或多种kindlin蛋白,K1主要存在于上皮细胞中,K3主要存在于造血细胞和内皮细胞中,而K2分布非常广泛。kindlins主要由一个4.1-erzin-radixin-moiesin(FERM)结构域组成,该结构域由一个脂质结合的plextrin-homology(PH)结构域横跨。小鼠和/或人类缺乏每一种kindlin都会产生严重的致病后果。kindlins最成熟的功能取决于它们参与激活整合素粘附受体的能力。这一功能取决于每种kindlin与整合素β亚基的结合,在整合素β亚基上,kindlin与talin合作,提高与认知的细胞外基质配体相互作用的热敏性。许多不同整合素的缺乏是致命的,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,整合素可以影响许多细胞反应。据报道,三种kindlins中每一种的表达变化都与乳腺癌有关,一些研究表明,kindlins是乳腺癌中上调最多的基因之一。K2 的异常功能与乳腺癌的关联尤其广泛,许多报告表明,K2 通过促进癌细胞增殖、存活、粘附、迁移、侵袭、上皮细胞向间质转化以及影响巨噬细胞的招募和表型,成为乳腺癌的主要驱动因素。这些关联表明,kindlins 及其功能是探索乳腺癌治疗的一个令人感兴趣的治疗靶点。
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