Kindlin-3 interacts with the ribosome and regulates c-Myc expression required for proliferation of chronic myeloid leukemia cells

Wee

Cell Adhesion & Migration

et al. 2016

Self Cite

Kindlins are a small family of 4.1-ezrin-radixin-moesin (FERM)-containing cytoplasmic proteins. Kindlin-3 is expressed in platelets, hematopoietic cells, and endothelial cells. Kindlin-3 promotes integrin activation, clustering and outside-in signaling. Aberrant expression of kindlin-3 was reported in melanoma and breast cancer. Intriguingly, kindlin-3 has been reported to either positively or negatively regulate cancer cell metastasis. In this study, we sought to clarify the expression of kindlin-3 in melanoma cells and its role in melanoma metastasis. Two widely used metastatic mouse and human melanoma cell lines B16-F10 and M10, respectively, were examined and found to lack kindlin-3 mRNA and protein expression. When kindlin-3 was ectopically expressed in these cells, cell migration was markedly reduced. These are attributed to aberrant Rac1 and RhoA activation and overt membrane ruffling. Our data demonstrate for the first time that despite its well established role as a positive regulator of integrin-mediated cell adhesion, aberrant expression of kindlin-3 could lead to imbalanced RhoGTPases signaling that impedes rather than promotes cell migration.

Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Expression of kindlin-3 in melanoma cells impedes cell migration and metastasis

Wee

Cell Adhesion & Migration

et al. 2016

Self Cite

“…Kindlin-3 was found to be associated with the pathology of chronic myeloid leukemia 96 and acute myeloid leukemia 95 . Qu and colleagues 96 showed that kindlin-3 may regulate the proliferation of human chronic myeloid leukemia K562 cells through the regulation of c-Myc protein expression and controlled the tumor growth of these cells in a xenograft model 96 . In another study, Wu and colleagues reported that levels of kindlin-3 increased in patients with acute myeloid leukemia after complete remission 95 .…”

Section: Association Of Kindlins With Cancermentioning

confidence: 99%

Of Kindlins and Cancer

Plow

Das

Białkowska

et al. 2016

Discoveries (Craiova)

Kindlins are 4.1-ezrin-ridixin-moesin (FERM) domain containing proteins. There are three kindlins in mammals, which share high sequence identity. Kindlin-1 is expressed primarily in epithelial cells, kindlin-2 is widely distributed and is particularly abundant in adherent cells, and kindlin-3 is expressed primarily in hematopoietic cells. These distributions are not exclusive; some cells express multiple kindlins, and transformed cells often exhibit aberrant expression, both in the isoforms and the levels of kindlins. Great interest in the kindlins has emerged from the recognition that they play major roles in controlling integrin function. In vitro studies, in vivo studies of mice deficient in kindlins, and studies of patients with genetic deficiencies of kindlins have clearly established that they regulate the capacity of integrins to mediate their functions. Kindlins are adaptor proteins; their function emanate from their interaction with binding partners, including the cytoplasmic tails of integrins and components of the actin cytoskeleton. The purpose of this review is to provide a brief overview of kindlin structure and function, a consideration of their binding partners, and then to focus on the relationship of each kindlin family member with cancer. In view of many correlations of kindlin expression levels and neoplasia and the known association of integrins with tumor progression and metastasis, we consider whether regulation of kindlins or their function would be attractive targets for treatment of cancer.

“…Although kindlin-3 is highly expressed in the hematopoietic system, there are only limited reports about its involvement in blood cell cancers, and a role of kindlin-3 phosphorylation in cancer cell is not known. Kindlin-3 was found to be associated with both acute and chronic myeloid leukemias (Wu et al, 2012;Qu et al, 2015). Kindlin-3 may influence proliferation of human chronic myeloid leukemia K562 cells through its regulation of c-Myc protein expression and kindlin-3 controlled the growth of these cells in a xenograft model (Qu et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Site-specific phosphorylation regulates the functions of kindlin-3 in a variety of cells

et al. 2019

Studies of isolated cells, mice, and humans have demonstrated the vital role of the FERM domain protein kindlin-3 in integrin activation in certain hematopoietic and non-hematopoietic cells, consequent to binding to integrin β-subunits. To explore regulatory mechanisms, we developed a monoclonal antibody that selectively recognizes the phosphorylated form of Ser484 (pS484) in kindlin-3. Activation of platelets, HEL megakaryocytic-like cells and BT549 breast cancer cells led to enhanced expression of pS484 as assessed by immunofluorescence or Western blotting. In platelets, pS484 rose rapidly and transiently upon stimulation. When a mutant form of kindlin-3, T482S484/AA kindlin-3, was transduced into mouse megakaryocytes, it failed to support activation of integrin αIIbβ3, whereas wild-type kindlin-3 did. In MDA-MB231 breast cancer cells, expression of T482S484/AA kindlin-3 suppressed cell spreading, migration, invasion, and VEGF production. Wild-type kindlin-3 expressing cells markedly increased tumor growth in vivo, whereas T482S484/AA kindlin-3 significantly blunted tumor progression. Thus, our data establish that a unique phosphorylation event in kindlin-3 regulates its cellular functions.