Abstract
The serine/threonine protein kinase AKT1 is a downstream target of the chemokine receptor 4 (CXCR4), and both proteins play a central role in the modulation of diverse cellular processes, including proliferation and cell survival. While in chronic myeloid leukemia (CML) the CXCR4 is downregulated, thereby promoting the mobilization of progenitor cells into blood, the receptor is highly expressed in breast cancer cells, favoring the migratory capacity of these cells. Recently, the LIM and SH3 domain protein 1 (LASP1) has been described as a novel CXCR4 binding partner and as a promoter of the PI3K/AKT pathway. In this study, we uncovered a direct binding of LASP1, phosphorylated at S146, to both CXCR4 and AKT1, as shown by immunoprecipitation assays, pull-down experiments, and immunohistochemistry data. In contrast, phosphorylation of LASP1 at Y171 abrogated these interactions, suggesting that both LASP1 phospho-forms interact. Finally, findings demonstrating different phosphorylation patterns of LASP1 in breast cancer and chronic myeloid leukemia may have implications for CXCR4 function and tyrosine kinase inhibitor treatment.
Highlights
The LIM and SH3 protein 1 (LASP1) was first identified in human metastatic lymph nodes in breast cancer patients [1]
After two days in cell culture, cells were tested for LIM and SH3 domain protein 1 (LASP1) depletion and AKT1-S473, AKT1-T308, and ERK phosphorylation by immunoblotting (Figure 1A)
The antibiotic doxycycline itself had no effects on AKT1 phosphorylatiosr results were obtained with different LASP1-depleted
Summary
The LIM and SH3 protein 1 (LASP1) was first identified in human metastatic lymph nodes in breast cancer patients [1]. Cells 2020, 9, 444 with an N-terminal LIM domain, followed by two nebulin-like repeats, a linker region with two phosphorylation sites at S146 and Y171, and a C-terminal SH3 domain, known to bind to proline-rich proteins like lipoma-preferred partner (LPP), zyxin, dynamin, vimentin, and zona occludens protein. Phosphorylation of LASP1 at S146 by protein kinase A or protein kinase G mainly attenuates binding to filamentous F-actin, zyxin, and lipoma protein partner (LPP), allowing subcellular relocalization of LASP1, [3] while phosphorylation at Y171 by c-Src and c-ABL non-receptor tyrosine kinases is associated with cell spreading [4] and apoptosis [5]. In chronic myeloid leukemia (CML), CXCR4 expression is down-regulated by the fusion protein BCR-ABL, and associated with a defective adhesion of CML cells to bone marrow stroma [8]
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