We are analyzing https://link.springer.com/article/10.1186/bcr2622.

Title:
Breast tumor kinase and extracellular signal-regulated kinase 5 mediate Met receptor signaling to cell migration in breast cancer cells | Breast Cancer Research
Description:
Introduction Breast tumor kinase (Brk/protein tyrosine kinase 6 (PTK6)) is a nonreceptor, soluble tyrosine kinase overexpressed in the majority of breast tumors. Previous work has placed Brk downstream of epidermal growth factor receptor (ErbB) activation and upstream of extracellular signal-regulated kinase 5 (ERK5) and p38 mitogen-activated protein (MAP) kinases. Herein we investigate the regulation of Brk kinase activity and cell migration in response to treatment of keratinocytes (HaCaT cells) and breast cancer cell lines (MDA-MB-231 and T47D cells) with hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP), peptide ligands for Met and Ron receptors, respectively. Methods In vitro kinase assays were performed to directly measure Brk kinase activity in response to MET and RON ligands. Transfection of Brk-targeted RNAi was used to knock down endogenous Brk or ERK5 in multiple cell lines. Kinase activities (downstream of MET signaling) were assayed by Western blotting using total and phospho-specific antibodies. Boyden chamber assays were used to measure cell migration in response to manipulation of Brk and downstream MET effectors. Rescue experiments were performed by knock down of endogenous Brk using RNAi (targeting the untranslated region (3′-UTR)) and transient transfection (re-expression) of either wild-type or kinase-inactive Brk. Results Brk gene silencing revealed that HGF, but not MSP, induced robust Brk-dependent cell migration. Brk and ERK5 copurified in HGF-induced protein complexes, and Brk/ERK5 complexes formed independently of Brk kinase activity. ERK5 was required for breast cancer cell but not keratinocyte cell migration, which became ERK1/2-dependent upon ERK5 knockdown. Notably, rescue experiments indicated that the kinase activity of Brk was not required for HGF-induced cell migration. Further, expression of either wild-type or kinase-inactive Brk in Brk-null MDA-MB-435 cells activated ERK5 and conferred increased HGF-induced cell migration. Conclusions These results have identified Brk and ERK5 as important downstream effectors of Met signaling to cell migration. Targeting ERK5 kinase activity or inhibiting the formation of Brk/ERK5 complexes may provide an additional means of blocking cell migration associated with breast cancer progression to metastasis.
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Keywords {🔍}

brk, cells, erk, cell, kinase, migration, hgf, breast, cancer, figure, sirna, pubmed, article, hacat, met, mdamb, control, google, scholar, signaling, cas, receptor, protein, activity, activation, hgfinduced, growth, expression, min, performed, treated, tyrosine, factor, ngml, results, antibodies, chamber, msp, expressing, assays, vehicle, increased, levels, western, total, required, egf, transiently, sam, phosphorylation,

Topics {✒️}

real-time quantitative rt-pcr km-brk-induced cell migration phosphate-buffered saline tween high-grade serous carcinoma grant r01 ca107547-01a1 article download pdf erk5-deficient mda-mb-231 cells terminal ser/thr kinase quantitative real-time pcr hepatocyte growth factor hgf-induced cell migration triple-negative breast cancer receptor protein-tyrosine kinase search identified brk heregulin-β1-induced activation madin-darby canine kidney protein g-agarose beads adapter protein lad/ribp brk-dependent cell migration key signalling nodes cell type-specific manner nuclear kinase sik/brk hgf-induced protein complexes mitogen-activated protein kinases epidermal growth factor mek5-dependent phosphorylation events mediate epithelial cell regulates heregulin-induced activation heregulin-β1 activate brk alter brk-protein complexes brk-dependent met signaling sik-knockout mice intracellular β-chain domain p38 mitogen-activated protein increased tumor growth induced cell migration c-met/hgf receptor breast tumor kinase km-brk-expressing cells breast cancer cell erk5 sirna-expressing cells growth factor stimulation mda-mb-231 cells failed full size image total-specific antibodies specific hgf-induced erk1/2 activation receptor tyrosine kinase receptor tyrosine kinase mapk signalling brk/akt protein complexes

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Chambers AF: MDA-MB-435 and M14 cell lines: identical but not M14 melanoma?

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WebPage:
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         description:Breast tumor kinase (Brk/protein tyrosine kinase 6 (PTK6)) is a nonreceptor, soluble tyrosine kinase overexpressed in the majority of breast tumors. Previous work has placed Brk downstream of epidermal growth factor receptor (ErbB) activation and upstream of extracellular signal-regulated kinase 5 (ERK5) and p38 mitogen-activated protein (MAP) kinases. Herein we investigate the regulation of Brk kinase activity and cell migration in response to treatment of keratinocytes (HaCaT cells) and breast cancer cell lines (MDA-MB-231 and T47D cells) with hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP), peptide ligands for Met and Ron receptors, respectively. In vitro kinase assays were performed to directly measure Brk kinase activity in response to MET and RON ligands. Transfection of Brk-targeted RNAi was used to knock down endogenous Brk or ERK5 in multiple cell lines. Kinase activities (downstream of MET signaling) were assayed by Western blotting using total and phospho-specific antibodies. Boyden chamber assays were used to measure cell migration in response to manipulation of Brk and downstream MET effectors. Rescue experiments were performed by knock down of endogenous Brk using RNAi (targeting the untranslated region (3′-UTR)) and transient transfection (re-expression) of either wild-type or kinase-inactive Brk. Brk gene silencing revealed that HGF, but not MSP, induced robust Brk-dependent cell migration. Brk and ERK5 copurified in HGF-induced protein complexes, and Brk/ERK5 complexes formed independently of Brk kinase activity. ERK5 was required for breast cancer cell but not keratinocyte cell migration, which became ERK1/2-dependent upon ERK5 knockdown. Notably, rescue experiments indicated that the kinase activity of Brk was not required for HGF-induced cell migration. Further, expression of either wild-type or kinase-inactive Brk in Brk-null MDA-MB-435 cells activated ERK5 and conferred increased HGF-induced cell migration. These results have identified Brk and ERK5 as important downstream effectors of Met signaling to cell migration. Targeting ERK5 kinase activity or inhibiting the formation of Brk/ERK5 complexes may provide an additional means of blocking cell migration associated with breast cancer progression to metastasis.
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         Hepatocyte Growth Factor
         HaCaT Cell
         T47D Cell
         Breast Cancer Cell Migration
         Cancer Research
         Oncology
         Surgical Oncology
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