Cell Migration Tom Paine March 16, 2010
Dec 28, 2015
Cell Migration
Tom PaineMarch 16, 2010
Will cover papers on single cell migration, adhesion-dependent trafficking and collective cell migration.
Single Cell Migration
Adhesion-DependentRaft Trafficking
Collective Cell Migration
Cell migration is a fundamental aspect of biology in both single and multi-cell organisms.
Slime mold Cancer Invasion
Tissue Repair
Single Cell Migration
Cell migration is a cycle with 6 main steps.
• Sense stimulus• Cell polarization and protrusion• Attach to substrate• Make room• Contract• Slide rear forward
Stimulus in form of chemo attractant gradient, involves signaling transduction.
• Signaling transduction sets up gradient.• Different molecules active in front and back.• Rho family GTPases, phosphoinositide 3
kinases, PI3ks, integrins, microtubules, vesicular transport
Polarization is mediated by Rho family proteins
Gradient Amplifiers• PI3Ks and PTENs allow cells to respond
directionally to very shallow chemoattractant gradients.
• Phosphoinositides PIP3 and PI(3,4)P2 rapid and highly polarized with chemo attractants
• PI3K localizes at leading edge• Generates PIP3/PI(3,4)P2• Break these systems and cells can migrate but
have problems moving up chemoattractant gradients
Cdc42
• Active in front– If you inhibit it or turn it on everywhere,
directionality of migration is hindered.• Can move Microtubule Organizing Center
(MTOC) and Golgi apparatus in front of the nucleus near the cell leading edge.– Position of MTOC maybe allow MT growth into
the lamellipodia– Make it easier for Golgi derived vesicles to get to
leading edge
GTP binding proteins
• It is activated by many chemoattractants• It can help localize Cdc42 at leading edge• Integrins may also contribute to localizing
Cdc42 activation
Actin Filaments Regulations
Cell Migration Model
Integrins
• Protrusions must attach to surroundings– Act as the ‘feet’
• Active integrins go to leading edge• GTPase Rap 1 or PKC increase integrin affinity• Cytoskeletal linker protein, talin promotes
integrin activation• Act as traction sites and mechano sensors
Rear end contraction
• So strong integrins may break off• Can even activate stretch activated calcium
channels
Adhesion Dependent Trafficking of Lipid Rafts
Lipid rafts contain GTPases such as Rac, Rho, and Cdc42.
• These are important in cell migration.• In anchorage-dependent cells, loss of
adhesion triggers cause raft compoent endocytosis.
• Rac1 and PI3K are down regulated.• Paper further studies adhesion dependent
endocytosis and exocytosis or raft components.
After detachment lipid rafts endocytosis and transport is actin and microtubule dependent.
Lipid rafts seem to be localized near gamma-tubulin, and the MTOC, but where specifically?
Experiment showed lipids rafts were actually in an area complimentary to the cis-Golgi marker.
Lipid rafts location constant, even when Golgi is dispersed by brefeldin A (BFA).
Lipid rafts also not localized to Smooth ER, as imaged by Autocrine motility factor receptor (AMF-R).
Also localized with Arf6, which regulates trafficking of Rac from recycling endosome to plasma membrane.
Lipid raft trafficking is dependent on actin, microtubules and Arf6.
Collective Cell Migration
Mechanisms of collective cell migration are similar to single cell migration, but split over many cells.
Collective cell migration has applications to morphogensis, tissue repair and cancer invasion.
More cells to work with
• Simultaneous coordinated polarization of many cells at leading edge
• Physical coupling drags cells forward• Lamella at cells at leading edge and
underneath cell collective• More remodelling of migration track, to
accommodate increased cell mass and volume• Retraction of multiple cells at rear
Cell-cell interactions, both physical and chemical become important.
Interactions with the stroma can also affect collective cell migration.
Focalized proteolysis
• Lots of cells need room to move.• Local matrix degradation and generation and
widening of paths are important.• Single cancer cells -> Small microtracks• Collective cells -> macrotracks (100s of
micrometers)
References
• Cell Migration: Integrating Signals from Front to Back – Ridley et al 2003
• Arf6 and microtubules in adhesion-dependent trafficking of lipid rafts – Balasubramanian et al 2007
• Mechanisms of collective cell migration at a glance – Ilina et al 2009
Questions?