Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE
De Piano, M.
Van Hemelrijck, M.
MetadataShow full item record
AbstractCancer invasion is a hallmark of metastasis. The mesenchymal mode of cancer cell invasion is mediated by elongated membrane protrusions driven by the assembly of branched F-actin networks. How deregulation of actin regulators promotes cancer cell invasion is still enigmatic. We report that increased expression and membrane localization of the actin regulator Lamellipodin correlate with reduced metastasis-free survival and poor prognosis in breast cancer patients. In agreement, we find that Lamellipodin depletion reduced lung metastasis in an orthotopic mouse breast cancer model. Invasive 3D cancer cell migration as well as invadopodia formation and matrix degradation was impaired upon Lamellipodin depletion. Mechanistically, we show that Lamellipodin promotes invasive 3D cancer cell migration via both actin-elongating Ena/VASP proteins and the Scar/WAVE complex, which stimulates actin branching. In contrast, Lamellipodin interaction with Scar/WAVE but not with Ena/VASP is required for random 2D cell migration. We identified a phosphorylation-dependent mechanism that regulates selective recruitment of these effectors to Lamellipodin: Abl-mediated Lamellipodin phosphorylation promotes its association with both Scar/WAVE and Ena/VASP, whereas Src-dependent phosphorylation enhances binding to Scar/WAVE but not to Ena/VASP. Through these selective, regulated interactions Lamellipodin mediates directional sensing of epidermal growth factor (EGF) gradients and invasive 3D migration of breast cancer cells. Our findings imply that increased Lamellipodin levels enhance Ena/VASP and Scar/WAVE activities at the plasma membrane to promote 3D invasion and metastasis.
CitationCarmona G, Perera U, Gillett C, Naba A, Law AL, Sharma VP, Wang J, Wyckoff J, Balsamo M, Mosis F, De Piano M, Monypenny J, Woodman N, McConnell RE, Mouneimne G, Van Hemelrijck M, Cao Y., Condeelis J, Hynes RO, Gertler FB, Krause M (2016) 'Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE', Oncogene, 35 (39), pp.5155-5169.
PublisherNature Publishing Group
PubMed Central IDPMC5031503
The following license files are associated with this item:
- Creative Commons
Except where otherwise noted, this item's license is described as Yellow - can archive pre-print (ie pre-refereeing)
- Lamellipodin promotes actin assembly by clustering Ena/VASP proteins and tethering them to actin filaments.
- Authors: Hansen SD, Mullins RD
- Issue date: 2015 Aug 21
- A phosphatidylinositol lipids system, lamellipodin, and Ena/VASP regulate dynamic morphology of multipolar migrating cells in the developing cerebral cortex.
- Authors: Yoshinaga S, Ohkubo T, Sasaki S, Nuriya M, Ogawa Y, Yasui M, Tabata H, Nakajima K
- Issue date: 2012 Aug 22
- WAVE binds Ena/VASP for enhanced Arp2/3 complex-based actin assembly.
- Authors: Havrylenko S, Noguera P, Abou-Ghali M, Manzi J, Faqir F, Lamora A, Guérin C, Blanchoin L, Plastino J
- Issue date: 2015 Jan 1
- Critical roles of phosphorylation and actin binding motifs, but not the central proline-rich region, for Ena/vasodilator-stimulated phosphoprotein (VASP) function during cell migration.
- Authors: Loureiro JJ, Rubinson DA, Bear JE, Baltus GA, Kwiatkowski AV, Gertler FB
- Issue date: 2002 Jul
- Ena/VASP proteins cooperate with the WAVE complex to regulate the actin cytoskeleton.
- Authors: Chen XJ, Squarr AJ, Stephan R, Chen B, Higgins TE, Barry DJ, Martin MC, Rosen MK, Bogdan S, Way M
- Issue date: 2014 Sep 8