An EGFR/PI3K/AKT axis promotes accumulation of the Rac1-GEF Tiam1 that is critical in EGFR-driven tumorigenesis.
Epidermal growth factor receptor (EGFR) signaling regulates cell growth and survival, and its overactivation drives cancer development. One important branch of EGFR signaling is through activation of GTPase Rac1, which further promotes cell proliferation, survival and cancer metastasis. Here, we show that EGFR activates Rac1 via inducing the accumulation of its specific guanine nucleotide exchange factor, T-cell lymphoma invasion and metastasis 1 (Tiam1) in non-small-cell lung cancer and colon cancer cells. Conversely, elevated Tiam1 is required for EGFR-induced tumorigenesis. In human lung adenocarcinoma and colon cancer specimens, Tiam1 expression strongly correlates with EGFR expression. We further reveal that AKT, a key downstream protein kinase of EGFR, phosphorylates Tiam1 at several consensus sites, facilitates the interaction of Tiam1 with scaffold proteins 14-3-3 and leads to an increase of Tiam1 stability. Subsequently, Tiam1 is dephosporylated and destabilized by PP2A. Together, our study identifies a bidirectional (phosphorylation and dephosphorylation) regulatory mechanism controlling Tiam1 stability and provides new insights on how EGFR signaling triggers Rac1 activation and cancer development.
MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua University, Beijing, China.|Tsinghua-Peking Center for Life Sciences, Beijing, China.
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G
Zhu
MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua University, Beijing, China.
Z
Z
Fan
School of Life Sciences, Peking University, Beijing, China.
M
M
Ding
National Institute of Biological Sciences, Beijing, China.
H
H
Zhang
MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua University, Beijing, China.|National Institute of Biological Sciences, Beijing, China.
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L
Mu
MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua University, Beijing, China.
Y
Y
Ding
Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China.
Y
Y
Zhang
Departments of General Surgery and Pathology, Chinese PLA General Hospital, Beijing, China.
B
B
Jia
National Institute of Biological Sciences, Beijing, China.
L
L
Chen
Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China.
Z
Z
Chang
MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua University, Beijing, China.
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W
Wu
D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D020662:Guanine Nucleotide Exchange Factors; C107953:RAC1 protein, human; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020830:rac1 GTP-Binding Protein