Self-organization of
protrusions and cell polarity
We have made significant strides in identifying the self-organizing positive and negative feedback loops that generate cell polarity. Cells normally generate polarity downstream of soluble extracellular cues, but we can initiate polarity by short-circuiting the receptor and directly interfacing with the core polarity machinery. We used this approach to identify a PIP3/Rac/actin positive feedback loop that organizes neutrophil polarity (Weiner et al., 2002). Similar positive feedback loops are thought to direct polarity in systems from yeast to Dictyostelium to neurons.
We are also investigating the molecular basis of the engine
of motility. We discovered that the leading edge of motile
cells is assembled from propagating waves of actin nucleators
containing the SCAR/WAVE complex. Similar to action
potentials, these nucleation waves are self-renewing and
generate their own inhibitors to produce directional movement.
This simple wave-generating circuit recapitulates many complex
behaviors of motile cells. More recently we have uncovered how
external gradients collaborate with intrinsic cell polarity to
control the spatial and temporal dynamics of actin nucleation
(Weiner et al., PLoS
Biol., 2007; Millius
et al, Current Biol., 2009). We can reproduce the
behavior of this circuit by a mathematical model that contains
a small number of variables and appears to represent a widely
conserved circuit for cell polarity. We are using a mixture of
cellular and biochemical experiments to dissect these higher
order feedback loops that organize polarity (Peng et al., MBOC,
2011; Houk
et al., Cell, 2012; Millius et al., J. Cell
Sci., 2012; Ku et al., Cell,
2012; Dandekar
et al., Phil. Trans. B. 2013; Diz-Munoz
et al., 2016).
(Rachel Brunetti, Brian Graziano, Anne Pipathsouk, Natasha
Puri, Suvrajit Saha, in collaboration with Kevin Thurley,
Steve Altschuler, Lani Wu)