title: PAK1 is a breast cancer oncogene that coordinately activates MAPK and MET signaling.
abstract: Activating mutations in the RAS family or BRAF frequently occur in many types of human cancers but are rarely detected in breast tumors. However, activation of the RAS-RAF-MEK-ERK MAPK pathway is commonly observed in human breast cancers, suggesting that other genetic alterations lead to activation of this signaling pathway. To identify breast cancer oncogenes that activate the MAPK pathway, we screened a library of human kinases for their ability to induce anchorage-independent growth in a derivative of immortalized human mammary epithelial cells (HMLE). We identified p21-activated kinase 1 (PAK1) as a kinase that permitted HMLE cells to form anchorage-independent colonies. PAK1 is amplified in several human cancer types, including 30--33% of breast tumor samples and cancer cell lines. The kinase activity of PAK1 is necessary for PAK1-induced transformation. Moreover, we show that PAK1 simultaneously activates MAPK and MET signaling; the latter via inhibition of merlin. Disruption of these activities inhibits PAK1-driven anchorage-independent growth. These observations establish PAK1 amplification as an alternative mechanism for MAPK activation in human breast cancer and credential PAK1 as a breast cancer oncogene that coordinately regulates multiple signaling pathways, the cooperation of which leads to malignant transformation.
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Y
authors: Y
authors: Shrestha
authors: E J
authors: EJ
authors: Schafer
authors: J S
authors: JS
authors: Boehm
authors: S R
authors: SR
authors: Thomas
authors: F
authors: F
authors: He
authors: J
authors: J
authors: Du
authors: S
authors: S
authors: Wang
authors: J
authors: J
authors: Barretina
authors: B A
authors: BA
authors: Weir
authors: J J
authors: JJ
authors: Zhao
authors: K
authors: K
authors: Polyak
authors: T R
authors: TR
authors: Golub
authors: R
authors: R
authors: Beroukhim
authors: W C
authors: WC
authors: Hahn
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics*; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009857:Oncogenes; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C515903:PAK1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D054462:p21-Activated Kinases; D020928:Mitogen-Activated Protein Kinases