Kindlins作为乳腺癌进展的调节剂

E. Plow, E. Pluskota, K. Białkowska
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引用次数: 1

摘要

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。在大多数细胞类型中发现一种或多种点燃蛋白,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,K2分布非常广泛。kindlins主要由4.1-erzin-radixin-moiesin (FERM)结构域组成,该结构域被脂质结合plextrin-homology (PH)结构域截断。在小鼠和/或人类中缺乏每一种kindlin都具有深远的致病后果。kindlins最完善的功能依赖于它们参与激活整合素粘附受体的能力。这种功能依赖于每个kindlin与整合素的β亚基的结合,在那里它与talin合作以增强与同源细胞外基质配体相互作用的亲切性。许多不同的整合素缺乏是致命的,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,kindlins可以影响许多细胞反应。据报道,三种kindlins中的每一种的表达变化都与乳腺癌有关,几项研究表明kindlins是乳腺癌中表达上调最多的基因之一。K2异常功能与乳腺癌的关联尤为广泛,许多报道表明,K2通过促进癌细胞增殖、存活、粘附、迁移、侵袭、上皮细胞向间质细胞的转化以及对巨噬细胞募集和表型的影响,是乳腺癌的主要驱动因素。这些关联表明,kindlins及其功能为探索乳腺癌治疗提供了一个有趣的治疗靶点。
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Kindlins as modulators of breast cancer progression
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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