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

Lamellipodia are crucial for haptotactic sensing and response.

Author information

1
UNC Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
2
UNC Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
3
UNC Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA Department of Pharmacology, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC 27599, USA.
4
UNC Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA Howard Hughes Medical Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
5
Department of Pharmacology, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC 27599, USA.
6
Department of Chemical & Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695, USA.
7
King's College London, Randall Institute, London SE1 8RT, UK.
8
UNC Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
9
UNC Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA Howard Hughes Medical Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA jbear@email.unc.edu.

Abstract

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

PMID:
27173494
PMCID:
PMC4920251
DOI:
10.1242/jcs.184507
[Indexed for MEDLINE]
Free PMC Article

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