dictyNews
Electronic Edition
Volume 39, number 29
October 11, 2013

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Abstracts
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Luo T, Mohan K, Iglesias PA, Robinson DN. 

Molecular mechanisms of cellular mechanosensing


Nat. Mater. 2013, in press.

Mechanical forces direct a host of cellular and tissue processes. 
Although much emphasis has been placed on cell-adhesion 
complexes as force sensors, the forces must nevertheless be 
transmitted through the cortical cytoskeleton. Yet how the actin 
cortex senses and transmits forces and how cytoskeletal proteins 
interact in response to the forces is poorly understood.  Here, by 
combining molecular and mechanical experimental perturbations 
with theoretical multiscale modelling, we decipher cortical 
mechanosensing from molecular to cellular scales. We show that 
forces are shared between myosin II and different actin crosslinkers, 
with myosin having potentiating or inhibitory effects on certain 
crosslinkers. Different types of cell deformation elicit distinct 
responses, with myosin and alpha-actinin responding to dilation, 
and filamin mainly reacting to shear. Our observations show that 
the accumulation kinetics of each protein may be explained by its 
molecular mechanisms, and that protein accumulation and the 
cell’s viscoelastic state can explain cell contraction against 
mechanical load.


Submitted by Douglas Robinson [[log in to unmask]]
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Phosphorylation of chemoattractant receptors regulates 
chemotaxis, actin reorganization and signal relay

Joseph A. Brzostowski1,*, Satoshi Sawai2, Orr Rozov1,‡, 
Xin-hua Liao3,§, Daisuke Imoto4, Carole A. Parent5 and 
Alan R. Kimmel3,*

1Laboratory of Immunogenetics Imaging Facility, NIAID/NIH, 
Rockville, MD 20852, USA
2Graduate School of Arts and Sciences, University of Tokyo and 
PRESTO, JST, Tokyo 153-8902, Japan
3Laboratory of Cellular and Developmental Biology, NIDDK/NIH, 
Bethesda, MD 20892, USA
4Graduate School of Arts and Sciences, University of Tokyo, 
Tokyo 153-8902, Japan
5Laboratory of Cellular and Molecular Biology, NCI/NIH, Bethesda, 
MD 20892, USA
*Authors for correspondence ([log in to unmask]; [log in to unmask])


J Cell Sci126, 4614-4626

Migratory cells, including mammalian leukocytes and Dictyostelium, 
use G-protein-coupled receptor (GPCR) signaling to regulate 
MAPK/ERK, PI3K, TORC2/AKT, adenylyl cyclase and actin 
polymerization, which collectively direct chemotaxis. Upon ligand 
binding, mammalian GPCRs are phosphorylated at cytoplasmic 
residues, uncoupling G-protein pathways, but activating other 
pathways. However, connections between GPCR phosphorylation 
and chemotaxis are unclear. In developing Dictyostelium, secreted 
cAMP serves as a chemoattractant, with extracellular cAMP 
propagated as oscillating waves to ensure directional migratory 
signals. cAMP oscillations derive from transient excitatory responses 
of adenylyl cyclase, which then rapidly adapts. We have studied 
chemotactic signaling in Dictyostelium that express non-
phosphorylatable cAMP receptors and show through chemotaxis 
modeling, single-cell FRET imaging, pure and chimeric population 
wavelet quantification, biochemical analyses and TIRF microscopy, 
that receptor phosphorylation is required to regulate adenylyl 
cyclase adaptation, long-range oscillatory cAMP wave production 
and cytoskeletal actin response. Phosphorylation defects thus 
promote hyperactive actin polymerization at the cell periphery, 
misdirected pseudopodia and the loss of directional chemotaxis. 
Our data indicate that chemoattractant receptor phosphorylation is 
required to co-regulate essential pathways for migratory cell 
polarization and chemotaxis. Our results significantly extend the 
understanding of the function of GPCR phosphorylation, providing 
strong evidence that this evolutionarily conserved mechanism is 
required in a signal attenuation pathway that is necessary to 
maintain persistent directional movement of Dictyostelium, 
neutrophils and other migratory cells.


Submitted by Joe Brzostowski [[log in to unmask]]
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[End dictyNews, volume 39, number 29]