ErbB2 promotes Src synthesis and stability: novel mechanisms of Src activation that confer breast cancer metastasis.
Activation of Src kinase plays important roles in the development of many neoplasias. Most of the previous Src studies focused on the deregulation of Src kinase activity. The deregulated Src protein synthesis and stability in mediating malignant phenotypes of cancer cells, however, have been neglected. While investigating the signal transduction pathways contributing to ErbB2-mediated metastasis, we found that ErbB2-activated breast cancer cells that had higher metastatic potentials also had increased Src activity compared with ErbB2 low-expressing cells. The increased Src activity in ErbB2-activated cells paralleled higher Src protein levels, whereas Src RNA levels were not significantly altered. Our studies revealed two novel mechanisms that are involved in Src protein up-regulation and activation by ErbB2: (a) ErbB2 increased Src translation through activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway and (b) ErbB2 increased Src stability most likely through the inhibition of the calpain protease. Furthermore, inhibition of Src activity by a Src-specific inhibitor, PP2, or a Src dominant-negative mutant dramatically reduced ErbB2-mediated cancer cell invasion in vitro and metastasis in an experimental metastasis animal model. Together, activation of ErbB2 and downstream signaling pathways can lead to increased Src protein synthesis and decreased Src protein degradation resulting in Src up-regulation and activation, which play critical roles in ErbB2-mediated breast cancer invasion and metastasis.
Tan
Ming
M
Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Li
Ping
P
Klos
Kristine S
KS
Lu
Jing
J
Lan
Keng-Hsueh
KH
Nagata
Yoichi
Y
Fang
Dexing
D
Jing
Tong
T
Yu
Dihua
D
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002154:Calpain / Q000037:antagonists & inhibitors; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D004789:Enzyme Activation; D004795:Enzyme Stability; D039642:Eukaryotic Initiation Factors; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D010749:Phosphoprotein Phosphatases / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D002154:Calpain; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D039642:Eukaryotic Initiation Factors; D010749:Phosphoprotein Phosphatases; D010750:Phosphoproteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016392:Proto-Oncogene Proteins pp60(c-src); D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; C087000:EIF4EBP1 protein, human; C499527:Eif4ebp1 protein, mouse; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C494918:AKT1 protein, human