Regulation of cell migration by the myosin IXb-Rho-GAP

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Cell migration is indispensable in multicellular organisms. In order to migrate, cells need to polarize and develop an extending front and a contractile back. Extension of the cell front is driven by actin polymerization and retraction of the back by acto-myosin II contraction. Actin polymerization and acto-myosin II contraction are controlled by the small, monomeric G-proteins Rac and Rho, respectively. The actin-based motorized signaling molecule myosin IXb (Myo9b, formerly myr 5) is a negative regulator of Rho. The loss of Myo9b leads to impaired cell migration both in vitro and in vivo. This impairment is due to inceased Rho and Rho-kinase (ROCK) activities. As we could show that Myo9b accumulates in cellular regions of actin polymerisation, we postulate that Myo9b is part of a local feedback loop initiated by Rac activation that induces downregulation of Rho activity specifically at the cell front. This hypothesis will be verified experimentally. Currently, it is not known whether motor- and RhoGAP-activities of Myo9b are subject to regulation and if so, how they could be regulated. The accumulation of Myo9b in regions of actin polymerisation depends on its motor activity. Whether there are any signals needed in addition to actin polymerisation for the recruitment of Myo9b will be investigated. Although Myo9b is a single-headed myosin, it is able to take multiple steps in vitro towards the plus-end of actin filaments without dissociating. Therefore, Myo9b might move its RhoGAP domain as a cargo along actin filaments towards the cell front. To achieve this, Myo9b would have to be able to move processively also in vivo with a velocity that is faster than the actin filaments are elongating. We propose to characterize the motor properties of Myo9b at the cell front in live cells by single molecule analysis. In summary, we hope to elucidate the exact molcecular mechanisms through which Myo9b regulates cell mgration and hence immune responses that critically depend on cell migration.