Effects of Fyn-related kinase activity on breast cancer cell proliferation, migration, invasion and colony formation

The human Fyn-related kinase (FRK) is a member of subfamily of Src-related kinases family. FRK is 54 kDa non-receptor tyrosine kinase protein composed of 505 amino acids. FRK consists of three functional domains: Src homology 3 (SH3), SH2 and kinase domain, as well as a putative tyrosine kinase re...

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Other Authors: Lukong, Kiven
Language:English
Published: 2015
Subjects:
FRK
Online Access:http://hdl.handle.net/10388/ETD-2015-01-1922
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spelling ndltd-USASK-oai-ecommons.usask.ca-10388-ETD-2015-01-19222015-01-31T04:53:09ZEffects of Fyn-related kinase activity on breast cancer cell proliferation, migration, invasion and colony formationFRKbreast cancerSTAT3The human Fyn-related kinase (FRK) is a member of subfamily of Src-related kinases family. FRK is 54 kDa non-receptor tyrosine kinase protein composed of 505 amino acids. FRK consists of three functional domains: Src homology 3 (SH3), SH2 and kinase domain, as well as a putative tyrosine kinase regulator at the C-terminus. FRK has a conserved auto-regulatory tyrosine residue within its kinase domain. It has been reported that FRK is repressed in about 30 % of human breast cancer samples. Over-expression of FRK in breast cancer cells of the mammary gland was shown to suppress cell growth by interacting, phosphorylating and stabilizing the tumor suppressor PTEN, thus inhibiting AKT/PI3K signaling. Although it has been suggested that FRK is a tumor suppressor gene, the effects of activated FRK on cell proliferation, migration and invasion are unclear. Likewise, the signaling pathways regulated by the activation of FRK have not been yet fully characterized. We hypothesize that the activation of FRK is essential for the regulation of its cellular functions. Mutation of the C-terminal auto-regulatory tyrosine 497 to phenylalanine (FRK-Y497F) resulted in the constitutive activation of FRK. We generated stable cell lines expressing either the FRK wild type (FRK-WT) or FRK-Y497F from triple negative breast cancer MDA-MB-231 cells. The introduction of FRK-Y497F in MDA-MB-231 cells significantly suppressed their proliferation, migration, invasiveness and colony formation as compared to cells that expressed the FRK-WT gene. Over-expression of either FRK-WT or FRK-Y497F in MDA-MB-231 cells inhibited the phosphorylation of AKT, STAT3, JNK and P38 MAPK as compared to either the MDA-MB-231 parental cells or those that were transfected with the empty vector. Our results suggested that FRK represses cell proliferation, migration, invasiveness and colony formation at least in part by the inhibiting the activation of AKT/PI3K, JAK-STAT and MAPK signaling pathways.Lukong, Kiven2015-01-30T12:00:10Z2015-01-30T12:00:10Z2015-012015-01-29January 2015textthesishttp://hdl.handle.net/10388/ETD-2015-01-1922eng
collection NDLTD
language English
sources NDLTD
topic FRK
breast cancer
STAT3
spellingShingle FRK
breast cancer
STAT3
Effects of Fyn-related kinase activity on breast cancer cell proliferation, migration, invasion and colony formation
description The human Fyn-related kinase (FRK) is a member of subfamily of Src-related kinases family. FRK is 54 kDa non-receptor tyrosine kinase protein composed of 505 amino acids. FRK consists of three functional domains: Src homology 3 (SH3), SH2 and kinase domain, as well as a putative tyrosine kinase regulator at the C-terminus. FRK has a conserved auto-regulatory tyrosine residue within its kinase domain. It has been reported that FRK is repressed in about 30 % of human breast cancer samples. Over-expression of FRK in breast cancer cells of the mammary gland was shown to suppress cell growth by interacting, phosphorylating and stabilizing the tumor suppressor PTEN, thus inhibiting AKT/PI3K signaling. Although it has been suggested that FRK is a tumor suppressor gene, the effects of activated FRK on cell proliferation, migration and invasion are unclear. Likewise, the signaling pathways regulated by the activation of FRK have not been yet fully characterized. We hypothesize that the activation of FRK is essential for the regulation of its cellular functions. Mutation of the C-terminal auto-regulatory tyrosine 497 to phenylalanine (FRK-Y497F) resulted in the constitutive activation of FRK. We generated stable cell lines expressing either the FRK wild type (FRK-WT) or FRK-Y497F from triple negative breast cancer MDA-MB-231 cells. The introduction of FRK-Y497F in MDA-MB-231 cells significantly suppressed their proliferation, migration, invasiveness and colony formation as compared to cells that expressed the FRK-WT gene. Over-expression of either FRK-WT or FRK-Y497F in MDA-MB-231 cells inhibited the phosphorylation of AKT, STAT3, JNK and P38 MAPK as compared to either the MDA-MB-231 parental cells or those that were transfected with the empty vector. Our results suggested that FRK represses cell proliferation, migration, invasiveness and colony formation at least in part by the inhibiting the activation of AKT/PI3K, JAK-STAT and MAPK signaling pathways.
author2 Lukong, Kiven
author_facet Lukong, Kiven
title Effects of Fyn-related kinase activity on breast cancer cell proliferation, migration, invasion and colony formation
title_short Effects of Fyn-related kinase activity on breast cancer cell proliferation, migration, invasion and colony formation
title_full Effects of Fyn-related kinase activity on breast cancer cell proliferation, migration, invasion and colony formation
title_fullStr Effects of Fyn-related kinase activity on breast cancer cell proliferation, migration, invasion and colony formation
title_full_unstemmed Effects of Fyn-related kinase activity on breast cancer cell proliferation, migration, invasion and colony formation
title_sort effects of fyn-related kinase activity on breast cancer cell proliferation, migration, invasion and colony formation
publishDate 2015
url http://hdl.handle.net/10388/ETD-2015-01-1922
_version_ 1716730032797253632