Breakthroughs

• Cytoskeletal proteins have overlapping functions. Detailed investigations of multiple gene deletions of myosins and actin binding proteins first demonstrated this now generally accepted concept (1).

• Cytoskeletal proteins and organelles dynamically relocalize within living cells during cytokinesis, motility, and phagocytosis. Actin, myosin, coronin, talin, cyclase-associated protein, and actin binding proteins move to related regions of the cell during each of these events (2). In addition, novel components of the cytoskeletal, including coronin, cortellexin, and scar having been discovered in Dictyostelium.

• Conventional myosin is required for cytokinesis. This was shown in D. discoideum over a decade ago and has recently been duplicated in yeast (3). Further studies of D. discoideum myosin heavy chain in vivo and as single molecules in vitro have provided many of the known characteristics of this molecular motor (4).

• Chemoattractants are sensed by G-protein coupled receptors. Over a decade ago, cloning and deletion of the cAMP receptors in D. discoideum showed that these receptors were essential for chemotaxis (5). It is now clear that a family of twenty G-protein linked "chemokine" receptors mediates chemotaxis in leukocytes.

• Gradient direction is sensed by selectively recruiting PH domains to the membrane. Neither surface receptors nor G-proteins are significantly clustered at the cell’s leading edge. In addition, the actin cytoskeleton is not required for PH domain recruitment (6). Many of these observations have recently been duplicated in mammalian leukocytes responding to chemokines.
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• PI(3) kinase is important for controlling cell movement, cell polarity, and chemotaxis. (7).
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• Eukaryotes use two-component histidine kinases for signal transduction. The variety of histidine kinases and response regulators in this organism has indicated the widespread occurrence of this mode of signaling in fungi, plants and other lower eucaryotes (8).

• A number of genes and signaling pathways found in higher eucaryotes but not  in yeast predate metazoans. These include the STAT signaling pathway,  the interplay of protein kinase A, GSK3 and in cell-type specific gene expression,  and genes of the apoptotic and Alzheimer's   disease pathways beclin and presenillin, respectively (9).

• G-protein coupled receptors can transduce signals without G-proteins. Receptor-mediated G-protein independent functions include calcium influx, MAPK activation, STAT and transcription factor activation (10). These observations fostered studies of mammalian cells that have verified the occurrence of GPCR-mediated G-protein-independent responses.

• Protein ubiquitination pathways are used in differentiation and pattern formation. Analysis of a MEKK identified the first defined in vivo substrate of a ubiquitin protease (UBP). This work and that on a "novel" F-box/WD40 repeat containing protein have identified new roles of ubiquitination in controlling patterning and cell-type determination (11).

• A chlorinated sterol like compound, differentiation-inducing factor (DIF) can determine cell fate. DIF was discovered nearly twenty years ago as an inducer of stalk cell differentiation (12). It has recently been found that DIF can change the differentiated state of a variety of mammalian cells.

• Spatial patterning can be regulated through serpentine receptor mediated tyrosine phosphorylation of GSK3.  (13)

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