ERK signaling promotes cell motility by inducing the localization of myosin 1E to lamellipodial tips

Signaling by extracellular signal-regulated kinase (ERK) plays an essential role in the induction of cell motility, but the precise mechanism underlying such regulation has remained elusive. We recently identified SH3P2 as a negative regulator of cell motility whose function is inhibited by p90 ribosomal S6 kinase (RSK)-mediated phosphorylation downstream of ERK. We here show that myosin 1E (Myo1E) is a binding partner of SH3P2 and that the interaction of the two proteins in the cytosol prevents the localization of Myo1E to the plasma membrane. Serum-induced phosphorylation of SH3P2 at Ser202 by RSK results in dissociation of Myo1E from SH3P2 in the cytosol and the subsequent localization of Myo1E to the tips of lamellipodia mediated by binding of its TH2 domain to F-actin. This translocation of Myo1E is essential for lamellipodium extension and consequent cell migration. The ERK signaling pathway thus promotes cell motility through regulation of the subcellular localization of Myo1E

(A) The mammary glands of 13-week-old virgin MMTV-BRCA1 (line 6) transgenic animals in diestrus were analyzed for transgene mRNA expression with a radiolabeled BRCA1 cDNA probe

<p><b>Copyright information:</b></p><p>Taken from "Effects of Transgene Expression on Murine Mammary Gland Development and Mutagen-Induced Mammary Neoplasia"</p><p></p><p>International Journal of Biological Sciences 2007;3(5):281-291.</p><p>Published online 25 Apr 2007</p><p>PMCID:PMC1865089.</p><p>© Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.</p> The ~5.6kb BRCA1 transgene mRNA is present in transgenic animals, but not in nontransgenic controls. Homozygous transgenic mice express more human BRCA1 mRNA than hemizygous mice. Hybridization to cyclophilin was performed to control for RNA loading on the gel. (B) The mammary glands of 13-week-old hemizygous MMTV-BRCA1t340 animals (line 2) were analyzed for transgene mRNA expression by Northern hybridization with a radiolabeled BRCA1t340 cDNA probe during different stages of the estrous cycle. BRCA1t340 expression is observed in transgenic mice, but not in nontransgenic controls. (C) The mammary glands of 13-week-old virgin hemizygous MMTV-BRCA1 (line 6) and MMTV-BRCA1sv (line 90) animals in diestrus were analyzed for transgene mRNA expression with a radiolabeled BRCA1 cDNA probe. Despite similar transgene copy numbers, MMTV-BRCA1sv (line 90) mRNA is at a significantly higher level than MMTV-BRCA1 (line 6) mRNA

Diagram of the BRCA1 cDNAs used for the generation of transgenic animals

<p><b>Copyright information:</b></p><p>Taken from "Effects of Transgene Expression on Murine Mammary Gland Development and Mutagen-Induced Mammary Neoplasia"</p><p></p><p>International Journal of Biological Sciences 2007;3(5):281-291.</p><p>Published online 25 Apr 2007</p><p>PMCID:PMC1865089.</p><p>© Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.</p> The expression of wild type BRCA1, BRCA1sv (70 amino acid N-terminal deletion), and BRCA1t340 (BRCA1 C-terminal truncation mutant) are controlled by the MMTV-LTR promoter. The BRCA1 cDNAs were each inserted into the third exon of the rabbit ß-globin gene (β-g). The bar indicates the RING finger motif, the hatched region corresponds to the nuclear localization signals and the negative symbols (-) indicate the negatively charged C-terminal domain with transactivation function