CoChat
Sign Up
Cited by 169Cellular Mechanics and InteractionsProtein Kinase Regulation and GTPase SignalingAxon Guidance and Neuronal Signaling

ERK-MAPK Drives Lamellipodia Protrusion by Activating the WAVE2 Regulatory Complex

Open access
Mendoza, Michelle C., Er, E. Emrah, Zhang, Wenjuan, Ballif, Bryan A., Elliott, Hunter L., Danuser, Gaudenz, Blenis, John·2011·Molecular Cell
DOI 10.1016/j.molcel.2011.02.031PMC PMC3078620
Open this paper in CoChat — free accountOpen PDF

Abstract

Cell movement begins with a leading edge protrusion, which is stabilized by nascent adhesions and retracted by mature adhesions. The ERK-MAPK (extracellular signal-regulated kinase-mitogen-activated protein kinase) localizes to protrusions and adhesions, but how it regulates motility is not understood. We demonstrate that ERK controls protrusion initiation and protrusion speed. Lamellipodial protrusions are generated via the WRC (WAVE2 regulatory complex), which activates the Arp2/3 actin nucleator for actin assembly. The WRC must be phosphorylated to be activated, but the sites and kinases that regulate its intermolecular changes and membrane recruitment are unknown. We show that ERK colocalizes with the WRC at lamellipodial leading edges and directly phosphorylates two WRC components: WAVE2 and Abi1. The phosphorylations are required for functional WRC interaction with Arp2/3 and actin during cell protrusion. Thus, ERK coordinates adhesion disassembly with WRC activation and actin polymerization to promote productive leading edge advancement during cell migration.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.molcel.2011.02.031

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • WAVE2 is phosphorylated by ERK or JNK at Ser308, Ser343, Thr346 and Ser351, and this phosphorylation is necessary for actin polymerization and the migration of cultured cell lines.

    “WAVE2 is phosphorylated by extracellular signal-regulated kinase (ERK) or Jun N-terminal kinase (JNK) at Ser308, Ser343, Thr346 and Ser351, and this phosphorylation is necessary for actin polymerization and the migration of cultured cell lines41–43.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [41]

    The Results (ERK Co-localizes with and Directly Phosphorylates the WRC; page unavailable) support ERK-dependent phosphorylation at the four named sites in HMECs, but the Discussion describes JNK phosphorylation only as a possibility for Ser343 and Thr346. The Results (ERK Phosphorylation of the WRC Regulates Interaction with Arp2/3 and Lamellipodial Protrusion; page unavailable) link phosphorylation to actin-polymerization cycles and protrusion, but do not establish that WAVE2 phosphorylation at these sites is necessary for migration: WAVE2 phosphosite mutants rescued Cos-7 cell motility in the presence of wild-type Abi1 and residual WAVE2. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Experiments with proteins containing mutations of these sites implicate a role of ABI1 phosphorylation in the release of the WCA domain and subsequent WAVE complex activation.

    “Experiments with proteins containing mutations of these sites implicate a role of ABI1 phosphorylation in the release of the WCA domain and subsequent WAVE complex activation36,41.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [41]

    The Results and Discussion report that mutations of Abi1 phosphorylation sites reduce WRC interaction with Arp2/3 and actin, supporting a role for Abi1 phosphorylation in WRC function. They do not show that Abi1 phosphorylation releases the WCA domain. The Introduction discusses release of the related VCA domain in connection with Rac binding and Abl phosphorylation of WAVE2, not Abi1 phosphorylation; page numbers are unavailable in our copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • ERK also phosphorylates multiple sites in ABI1, including Ser183, Ser216, Ser225, Thr265, Ser267, Ser392, Thr394 and Ser410.

    “ERK also phosphorylates multiple sites in ABI1, including Ser183, Ser216, Ser225, Thr265, Ser267, Ser392, Thr394 and Ser41041 (Fig. 3d).”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [41]

    The Results section reports ERK-dependent phosphorylation of Abi1 and shows that mutating all eight listed sites nearly abolished phosphorylation by ERK2. But it directly identifies S183 and S225, calls S216 suspected rather than definitive, and describes T265, S267, S392, T394 and S410 as predicted ERK sites. The evidence therefore supports the group-level claim more strongly than it establishes phosphorylation at each named site. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 49

  1. Abe Y Yoon SO Kubota K Mendoza MC Gygi SP Blenis J p90 ribosomal S6 kinase and p70 ribosomal S6 kinase link phosphorylation of the eukaryotic chaperonin containing TCP-1 to growth factor, insulin, and nutrient signaling J Biol Chem 2009 284 14939 14948 19332537 PMC2685676
  2. Ballif BA Carey GR Sunyaev SR Gygi SP Large-scale identification and evolution indexing of tyrosine phosphorylation sites from murine brain J Proteome Res 2008 7 311 318 18034455
  3. Brahmbhatt AA Klemke RL ERK and RhoA differentially regulate pseudopodia growth and retraction during chemotaxis J Biol Chem 2003 278 13016 13025 12571246
  4. Chen Z Borek D Padrick SB Gomez TS Metlagel Z Ismail AM Umetani J Billadeau DD Otwinowski Z Rosen MK Structure and control of the actin regulatory WAVE complex Nature 2010 468 533 538 21107423 PMC3085272
  5. Choi CK Vicente-Manzanares M Zareno J Whitmore LA Mogilner A Horwitz AR Actin and alpha-actinin orchestrate the assembly and maturation of nascent adhesions in a myosin II motor-independent manner Nat Cell Biol 2008 10 1039 1050 19160484 PMC2827253
  6. Coles LC Shaw PE PAK1 primes MEK1 for phosphorylation by Raf-1 kinase during cross-cascade activation of the ERK pathway Oncogene 2002 21 2236 2244 11948406
  7. Danson CM Pocha SM Bloomberg GB Cory GO Phosphorylation of WAVE2 by MAP kinases regulates persistent cell migration and polarity J Cell Sci 2007 120 4144 4154 18032787 PMC2690415
  8. Derivery E Lombard B Loew D Gautreau A The Wave complex is intrinsically inactive Cell Motil Cytoskeleton 2009 66 777 790 19206172
  9. Dimitri CA Dowdle W MacKeigan JP Blenis J Murphy LO Spatially separate docking sites on ERK2 regulate distinct signaling events in vivo Curr Biol 2005 15 1319 1324 16051177
  10. Eblen ST Slack JK Weber MJ Catling AD Rac-PAK signaling stimulates extracellular signal-regulated kinase (ERK) activation by regulating formation of MEK1-ERK complexes Mol Cell Biol 2002 22 6023 6033 12167697 PMC134005
  11. Fincham VJ James M Frame MC Winder SJ Active ERK/MAP kinase is targeted to newly forming cell-matrix adhesions by integrin engagement and v-Src Embo J 2000 19 2911 2923 10856236 PMC203361
  12. Giannone G Dubin-Thaler BJ Rossier O Cai Y Chaga O Jiang G Beaver W Dobereiner HG Freund Y Borisy G Lamellipodial actin mechanically links myosin activity with adhesion-site formation Cell 2007 128 561 575 17289574 PMC5219974
  13. Heasman SJ Ridley AJ Mammalian Rho GTPases: new insights into their functions from in vivo studies Nat Rev Mol Cell Biol 2008 9 690 701 18719708
  14. Hutti JE Jarrell ET Chang JD Abbott DW Storz P Toker A Cantley LC Turk BE A rapid method for determining protein kinase phosphorylation specificity Nat Methods 2004 1 27 29 15782149
  15. Insall R Machesky L Actin Dynamics at the Leading Edge: From Simple Machinery to Complex Networks Developmental Cell 2009 17 310 322 19758556
  16. Ishibe S Joly D Zhu X Cantley LG Phosphorylation-dependent paxillin-ERK association mediates hepatocyte growth factor-stimulated epithelial morphogenesis Mol Cell 2003 12 1275 1285 14636584
  17. Ismail AM Padrick SB Chen B Umetani J Rosen MK The WAVE regulatory complex is inhibited Nat Struct Mol Biol 2009 16 561 563 19363480 PMC2716658
  18. Ji L Lim J Danuser G Fluctuations of intracellular forces during cell protrusion Nat Cell Biol 2008 10 1393 1400 19011623 PMC2597050
  19. Kim Y Sung JY Ceglia I Lee KW Ahn JH Halford JM Kim AM Kwak SP Park JB Ho Ryu S Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology Nature 2006 442 814 817 16862120
  20. Klemke RL Cai S Giannini AL Gallagher PJ de Lanerolle P Cheresh DA Regulation of cell motility by mitogen-activated protein kinase J Cell Biol 1997 137 481 492 9128257 PMC2139771
  21. Kolsch V Charest PG Firtel RA The regulation of cell motility and chemotaxis by phospholipid signaling J Cell Sci 2008 121 551 559 18287584 PMC2671295
  22. Lachmanovich E Shvartsman DE Malka Y Botvin C Henis YI Weiss AM Co-localization analysis of complex formation among membrane proteins by computerized fluorescence microscopy: application to immunofluorescence co-patching studies J Microsc 2003 212 122 131 14629561
  23. Lebensohn AM Kirschner MW Activation of the WAVE complex by coincident signals controls actin assembly Mol Cell 2009 36 512 524 19917258 PMC2818508
  24. Leng Y Zhang J Badour K Arpaia E Freeman S Cheung P Siu M Siminovitch K Abelson-interactor-1 promotes WAVE2 membrane translocation and Abelson-mediated tyrosine phosphorylation required for WAVE2 activation Proc Natl Acad Sci U S A 2005 102 1098 1103 15657136 PMC545868
  25. Liu ZX Yu CF Nickel C Thomas S Cantley LG Hepatocyte growth factor induces ERK-dependent paxillin phosphorylation and regulates paxillin-focal adhesion kinase association J Biol Chem 2002 277 10452 10458 11784715
  26. Machacek M Danuser G Morphodynamic profiling of protrusion phenotypes Biophys J 2006 90 1439 1452 16326902 PMC1367294
  27. McKay MM Morrison DK Integrating signals from RTKs to ERK/MAPK Oncogene 2007 26 3113 3121 17496910
  28. Murphy LO Smith S Chen RH Fingar DC Blenis J Molecular interpretation of ERK signal duration by immediate early gene products Nat Cell Biol 2002 4 556 564 12134156
  29. Nakanishi O Suetsugu S Yamazaki D Takenawa T Effect of WAVE2 phosphorylation on activation of the Arp2/3 complex J Biochem 2007 141 319 325 17202194
  30. Nayal A Webb DJ Brown CM Schaefer EM Vicente-Manzanares M Horwitz AR Paxillin phosphorylation at Ser273 localizes a GIT1-PIX-PAK complex and regulates adhesion and protrusion dynamics J Cell Biol 2006 173 587 589 16717130 PMC2063867
  31. Obenauer JC Cantley LC Yaffe MB Scansite 2.0: Proteome-wide prediction of cell signaling interactions using short sequence motifs Nucleic Acids Res 2003 31 3635 3641 12824383 PMC168990
  32. Padrick SB Cheng HC Ismail AM Panchal SC Doolittle LK Kim S Skehan BM Umetani J Brautigam CA Leong JM Hierarchical regulation of WASP/WAVE proteins Mol Cell 2008 32 426 438 18995840 PMC2680354
  33. Padrick SB Rosen MK Physical mechanisms of signal integration by WASP family proteins Annu Rev Biochem 2010 79 707 735 20533885 PMC3017724
  34. Pocha SM Cory GO WAVE2 is regulated by multiple phosphorylation events within its VCA domain Cell Motil Cytoskeleton 2009 66 36 47 19012317 PMC2798068
  35. Pollard TD Cooper JA Actin, a central player in cell shape and movement Science 2009 326 1208 1212 19965462 PMC3677050
  36. Ponti A Machacek M Gupton SL Waterman-Storer CM Danuser G Two distinct actin networks drive the protrusion of migrating cells Science 2004 305 1782 1786 15375270
  37. Pullikuth AK Catling AD Scaffold mediated regulation of MAPK signaling and cytoskeletal dynamics: a perspective Cell Signal 2007 19 1621 1632 17553668 PMC2233890
  38. Scott MG Pierotti V Storez H Lindberg E Thuret A Muntaner O Labbe-Jullie C Pitcher JA Marullo S Cooperative regulation of extracellular signal-regulated kinase activation and cell shape change by filamin A and beta-arrestins Mol Cell Biol 2006 26 3432 3445 16611986 PMC1447405
  39. Segall JE Tyerech S Boselli L Masseling S Helft J Chan A Jones J Condeelis J EGF stimulates lamellipod extension in metastatic mammary adenocarcinoma cells by an actin-dependent mechanism Clin Exp Metastasis 1996 14 61 72 8521618
  40. Shaul YD Seger R The MEK/ERK cascade: from signaling specificity to diverse functions Biochim Biophys Acta 2007 1773 1213 1226 17112607
  41. Slack-Davis JK Eblen ST Zecevic M Boerner SA Tarcsafalvi A Diaz HB Marshall MS Weber MJ Parsons JT Catling AD PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation J Cell Biol 2003 162 281 291 12876277 PMC2172784
  42. Smith SD Jaffer ZM Chernoff J Ridley AJ PAK1-mediated activation of ERK1/2 regulates lamellipodial dynamics J Cell Sci 2008 121 3729 3736 18940914 PMC2702775
  43. Stuart JR Gonzalez FH Kawai H Yuan ZM c-Abl interacts with the WAVE2 signaling complex to induce membrane ruffling and cell spreading J Biol Chem 2006 281 31290 31297 16899465
  44. Suetsugu S Kurisu S Oikawa T Yamazaki D Oda A Takenawa T Optimization of WAVE2 complex-induced actin polymerization by membrane-bound IRSp53, PIP(3), and Rac J Cell Biol 2006 173 571 585 16702231 PMC2063866
  45. Takenawa T Suetsugu S The WASP-WAVE protein network: connecting the membrane to the cytoskeleton Nat Rev Mol Cell Biol 2007 8 37 48 17183359
  46. Vicente-Manzanares M Ma X Adelstein RS Horwitz AR Non-muscle myosin II takes centre stage in cell adhesion and migration Nat Rev Mol Cell Biol 2009 10 778 790 19851336 PMC2834236
  47. Vomastek T Iwanicki MP Schaeffer HJ Tarcsafalvi A Parsons JT Weber MJ RACK1 targets the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway to link integrin engagement with focal adhesion disassembly and cell motility Mol Cell Biol 2007 27 8296 8305 17908799 PMC2169169
  48. Webb DJ Donais K Whitmore LA Thomas SM Turner CE Parsons JT Horwitz AF FAK-Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly Nat Cell Biol 2004 6 154 161 14743221
  49. Zappaterra MD Lisgo SN Lindsay S Gygi SP Walsh CA Ballif BA A comparative proteomic analysis of human and rat embryonic cerebrospinal fluid J Proteome Res 2007 6 3537 3548 17696520

Cited by

Sorted by citations

Authors
Mendoza, M. C., Er, E. E., Zhang, W., Ballif, B. A., Elliott, H. L., Danuser, G., & Blenis, J.
Affiliations
  • Harvard University (US)
  • Peking University (CN)
  • University of Vermont (US)
  • Scripps Research Institute (US)
Corresponding author
  • Mendoza, Michelle C.
  • Blenis, John
ORCID
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2011-03
Volume
41
Issue
6
Pages
661-671
ISSN
1097-2765 (ISSN-L)
DOI
10.1016/j.molcel.2011.02.031
PMC
PMC3078620
OpenAlex
W2058258724
Cited by
169
References
2
Citations by year
2026: 6 · 2025: 10 · 2024: 13 · 2023: 11 · 2022: 14 · 2021: 16 · 2020: 12 · 2019: 6 · 2018: 8 · 2017: 9 · 2016: 14 · 2015: 11 · 2014: 9 · 2013: 16 · 2012: 8
FWCI
5.63
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5u54gm064346-10)
  • National Cancer Institute (R37CA046595)
  • National Institute of General Medical Sciences (U54-GM064346, U54 GM 64346)
  • National Center for Research Resources (P20RR016462)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
Keywords
ERK signaling, lamellipodia, cell migration, ABI1, Arp2/3 complex, actin polymerization, leading edge protrusion
MeSH terms
Actins, Cell Movement, Cells, Cultured, Cytoskeletal Proteins, Epithelial Cells, Humans, Phosphorylation, Pseudopodia, Extracellular Signal-Regulated MAP Kinases, Adaptor Proteins, Signal Transducing, Wiskott-Aldrich Syndrome Protein Family, Actin-Related Protein 2-3 Complex

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review