Distinct mechanisms regulate cell migration in confined versus unconfined spaces

Microchannel Migration Rac1myosin IIPKA;Cell Biology

Hung, Wei-chienPineda, Fernando ;

Johns Hopkins University

关键词: Microchannel Migration Rac1myosin IIPKA;    Cell Biology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/60320/HUNG-DISSERTATION-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Using a microchannel assay, we demonstrate that cells adopt distinct signaling strategies to modulate cell migration in different physical microenvironments. We studied α4β1 integrin-mediated signaling, which regulates cell migration pertinent to embryonic development, leukocyte trafficking and melanoma invasion. We show that α4β1 integrin promotes cell migration through both unconfined and confined spaces. However, unlike unconfined (2D) migration, which depends on enhanced Rac1 activity achieved by preventing α4/paxillin binding, confined migration requires myosin II-driven contractility, which is increased when Rac1 is inhibited by α4/paxillin binding. This Rac1-myosin II crosstalk mechanism also controls migration of fibroblast-like cells lacking α4β1 integrin, in which Rac1 and myosin II modulate unconfined and confined migration, respectively. We further demonstrate the distinct roles of myosin II isoforms, MIIA and MIIB, which are primarily required for confined and unconfined migration, respectively. Protein kinase A (PKA) works upstream to regulate phosphorylation of verious proteins and enzymes, including α4β1 integrin. It has been reported that PKA tightly regulates wide array of (patho)physiological functions. We have further employed FRET-based-PKA reporter (AKAR4-Kras) to investigate how cells modulate PKA activity spatiotemporally. We have found that the interplay of PKA, Rac1/myosin II, and cytoskeleton-related molecules determines efficient migration in response to various degrees of physical constraint. This work provides a paradigm for the plasticity of cells migrating through different physical microenvironments.