Lamellipodia are crucial for haptotactic sensing and response

J Cell Sci. 2016 Jun 15;129(12):2329-42. doi: 10.1242/jcs.184507. Epub 2016 May 12.


Haptotaxis is the process by which cells respond to gradients of substrate-bound cues, such as extracellular matrix proteins (ECM); however, the cellular mechanism of this response remains poorly understood and has mainly been studied by comparing cell behavior on uniform ECMs with different concentrations of components. To study haptotaxis in response to gradients, we utilized microfluidic chambers to generate gradients of the ECM protein fibronectin, and imaged the cell migration response. Lamellipodia are fan-shaped protrusions that are common in migrating cells. Here, we define a new function for lamellipodia and the cellular mechanism required for haptotaxis - differential actin and lamellipodial protrusion dynamics lead to biased cell migration. Modest differences in lamellipodial dynamics occurring over time periods of seconds to minutes are summed over hours to produce differential whole cell movement towards higher concentrations of fibronectin. We identify a specific subset of lamellipodia regulators as being crucial for haptotaxis. Numerous studies have linked components of this pathway to cancer metastasis and, consistent with this, we find that expression of the oncogenic Rac1 P29S mutation abrogates haptotaxis. Finally, we show that haptotaxis also operates through this pathway in 3D environments.

Keywords: Arp2/3; Directed migration; Haptotaxis; Lamellipodia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin-Related Protein 2-3 Complex / metabolism
  • Actins / metabolism
  • Animals
  • Chemotaxis* / drug effects
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibronectins / pharmacology*
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism
  • Focal Adhesions / metabolism
  • Guanine Nucleotide Exchange Factors / metabolism
  • Integrin beta1 / metabolism
  • Mice
  • Models, Biological
  • Pseudopodia / metabolism*
  • Signal Transduction / drug effects
  • T-Lymphoma Invasion and Metastasis-inducing Protein 1
  • Wiskott-Aldrich Syndrome Protein / metabolism
  • Wiskott-Aldrich Syndrome Protein Family / metabolism
  • rac GTP-Binding Proteins / metabolism
  • src-Family Kinases / metabolism


  • Actin-Related Protein 2-3 Complex
  • Actins
  • Fibronectins
  • Guanine Nucleotide Exchange Factors
  • Integrin beta1
  • T-Lymphoma Invasion and Metastasis-inducing Protein 1
  • Tiam1 protein, mouse
  • Wiskott-Aldrich Syndrome Protein
  • Wiskott-Aldrich Syndrome Protein Family
  • Focal Adhesion Protein-Tyrosine Kinases
  • src-Family Kinases
  • rac GTP-Binding Proteins