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Sorting nexin 2-mediated membrane trafficking of c-Met contributes to sensitivity of molecular-targeted drugs.

ABSTRACT: The sorting nexin (SNX) family is a diverse group of cytoplasmic and membrane-associated proteins that are involved in membrane-trafficking steps within the endocytotic network. SNX1 and SNX2 are components of the mammalian retromer complex and they also play critical roles in the membrane trafficking of growth factor receptors including epidermal growth factor receptor (EGFR) and c-Met. The human lung cancer cell lines, which harbor activating mutations in the kinase domain of EGFR gene, are sensitive to EGFR-targeted drugs gefitinib or erlotinib. However, a lung cancer cell line harboring gene amplification of c-Met is sensitive to the c-Met-targeted drug SU11274 but not to EGFR-targeted drugs. C-Met overexpression is identified as one of the bypass mechanisms for acquired resistance to EGFR-targeted drugs. Here we show that the siRNA-mediated knockdown of SNX2 decreases the cell-surface localization of c-Met, but not that of EGFR, resulting in lysosomal degradation of the c-Met protein. SNX2 specifically interacts with c-Met and treatment with lysosomal inhibitors almost completely annihilates downregulation of c-Met protein by SNX2 knockdown. Therefore, silencing of SNX2 markedly alters sensitivity to anticancer drugs targeted to c-Met (SU11274) and EGFR (gefitinib and erlotinib) through promotion of compensatory activation of the EGFR pathway in lung cancer cells. These findings suggest that development of drugs targeting SNX2 could be useful in overcoming drug resistance to EGFR-targeted drugs in lung cancer cells harboring c-Met gene amplification.

SUBMITTER: Ogi S

PROVIDER: S-EPMC7657160 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Sorting nexin 2-mediated membrane trafficking of c-Met contributes to sensitivity of molecular-targeted drugs.

Ogi Sayaka S Fujita Hideaki H Kashihara Masaki M Yamamoto Chizuko C Sonoda Kahori K Okamoto Isamu I Nakagawa Kazuhiko K Ohdo Shigehiro S Tanaka Yoshitaka Y Kuwano Michihiko M Ono Mayumi M

Cancer science 20130308 5

The sorting nexin (SNX) family is a diverse group of cytoplasmic and membrane-associated proteins that are involved in membrane-trafficking steps within the endocytotic network. SNX1 and SNX2 are components of the mammalian retromer complex and they also play critical roles in the membrane trafficking of growth factor receptors including epidermal growth factor receptor (EGFR) and c-Met. The human lung cancer cell lines, which harbor activating mutations in the kinase domain of EGFR gene, are se ...[more]

PMID: 23360489

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Project description:Bone homeostasis is a complex, multi-step process, which is based primarily on a tightly orchestrated interplay between bone formation and bone resorption that is executed by osteoblasts and osteoclasts (OCLs), respectively. The essential physiological balance between these cells is maintained and controlled at multiple levels, ranging from regulated gene expression to endocrine signals, yet the underlying cellular and molecular mechanisms are still poorly understood. One approach for deciphering the mechanisms that regulate bone homeostasis is the characterization of relevant pathological states in which this balance is disturbed. In this article we describe one such "error of nature," namely the development of acute recessive osteopetrosis (ARO) in humans that is caused by mutations in sorting nexin 10 (SNX10) that affect OCL functioning. We hypothesize here that, by virtue of its specific roles in vesicular trafficking, SNX10 serves as a key selective regulator of the composition of diverse membrane compartments in OCLs, thereby affecting critical processes in the sequence of events that link the plasma membrane with formation of the ruffled border and with extracellular acidification. As a result, SNX10 determines multiple features of these cells either directly or, as in regulation of cell-cell fusion, indirectly. This hypothesis is further supported by the similarities between the cellular defects observed in OCLs form various models of ARO, induced by mutations in SNX10 and in other genes, which suggest that mutations in the known ARO-associated genes act by disrupting the same plasma membrane-to-ruffled border axis, albeit to different degrees. In this article, we describe the population genetics and spread of the original arginine-to-glutamine mutation at position 51 (R51Q) in SNX10 in the Palestinian community. We further review recent studies, conducted in animal and cellular model systems, that highlight the essential roles of SNX10 in critical membrane functions in OCLs, and discuss possible future research directions that are needed for challenging or substantiating our hypothesis.

Dataset Information

Sorting nexin 2-mediated membrane trafficking of c-Met contributes to sensitivity of molecular-targeted drugs.

Publications

Sorting nexin 2-mediated membrane trafficking of c-Met contributes to sensitivity of molecular-targeted drugs.

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