title: The kinase LMTK3 promotes invasion in breast cancer through GRB2-mediated induction of integrin β₁.
abstract: Lemur tyrosine kinase 3 (LMTK3) is associated with cell proliferation and endocrine resistance in breast cancer. We found that, in cultured breast cancer cell lines, LMTK3 promotes the development of a metastatic phenotype by inducing the expression of genes encoding integrin subunits. Invasive behavior in various breast cancer cell lines positively correlated with the abundance of LMTK3. Overexpression of LMTK3 in a breast cancer cell line with low endogenous LMTK3 abundance promoted actin cytoskeleton remodeling, focal adhesion formation, and adhesion to collagen and fibronectin in culture. Using SILAC (stable isotope labeling by amino acids in cell culture) proteomic analysis, we found that LMTK3 increased the abundance of integrin subunits α5 and β1, encoded by ITGA5 and ITGB1. This effect depended on the CDC42 Rho family guanosine triphosphatase, which was in turn activated by the interaction between LMTK3 and growth factor receptor-bound protein 2 (GRB2), an adaptor protein that mediates receptor tyrosine kinase-induced activation of RAS and downstream signaling. Knockdown of GRB2 suppressed LMTK3-induced CDC42 activation, blocked ITGA5 and ITGB1 expression promoted by the transcription factor serum response factor (SRF), and reduced invasive activity. Furthermore, abundance of LMTK3 positively correlated with that of the integrin β1 subunit in breast cancer patient's tumors. Our findings suggest a role for LMTK3 in promoting integrin activity during breast cancer progression and metastasis.
authors.affiliation: Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK.
authors.forename: Yichen
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK. Department of Physiology, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Lei C
authors.initials: LC
authors.lastname: Lit
authors.affiliation: Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK.
authors.forename: Arnhild
authors.initials: A
authors.lastname: Grothey
authors.affiliation: Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK. Institute of Pharmaceutical Science, Kings College London, Britannia House, 7 Trinity Street, London SE1 1DB, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Athanasiadou
authors.affiliation: Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK.
authors.forename: Marianna
authors.initials: M
authors.lastname: Kiritsi
authors.affiliation: Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK.
authors.forename: Ylenia
authors.initials: Y
authors.lastname: Lombardo
authors.affiliation: Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK.
authors.forename: Adam E
authors.initials: AE
authors.lastname: Frampton
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham and Nottingham University Hospital NHS Trust, Hucknall Road, Nottingham NG5 1PB, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Green
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham and Nottingham University Hospital NHS Trust, Hucknall Road, Nottingham NG5 1PB, UK.
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK.
authors.forename: Simak
authors.initials: S
authors.lastname: Ali
authors.affiliation: Division of Medical Oncology, University of Southern California, Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA 90033, USA.
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.affiliation: Institute of Pharmaceutical Science, Kings College London, Britannia House, 7 Trinity Street, London SE1 1DB, UK.
authors.forename: Maya
authors.initials: M
authors.lastname: Thanou
authors.affiliation: Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK.
authors.forename: Justin
authors.initials: J
authors.lastname: Stebbing
authors.affiliation: Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK. g.giamas@imperial.ac.uk.
authors.forename: Georgios
authors.initials: G
authors.lastname: Giamas
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D005260:Female; D051380:GRB2 Adaptor Protein / Q000502:physiology*; D006801:Humans; D019012:Integrin beta1 / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D019012:Integrin beta1; D008565:Membrane Proteins; C560359:LMTK3 protein, human; D017346:Protein Serine-Threonine Kinases