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Review the Dynamins Proc. Natl. Acad. Sci. USA Vol. 94, pp. 377–384, January 1997 Review The dynamins: Redundant or distinct functions for an expanding family of related GTPases? Raul Urrutia, John R. Henley, Tiffany Cook, and Mark A. McNiven* Center for Basic Research in Digestive Diseases, Department of Biochemistry and Molecular Biology, and Department of Molecular Neuroscience, Mayo Clinic, Rochester, MN 55905 Communicated by Thomas S. Reese, National Institute of Neurological Disorders and Stroke, Bethesda, MD, October 29, 1996 (received for review October 1995) ABSTRACT In the 7 years since dynamin was first isolated gene revealed an 81% similarity to the brain dynamin cDNA from bovine brain in search of novel microtubule-based motors, (8, 9). The finding that dynamin is the homologue of the shibire our understanding of this enzyme has expanded significantly. We gene product was a significant step toward understanding the now know that brain dynamin belongs to a family of large functional role of these proteins. Important information on the GTPases, which mediate vesicle trafficking. Furthermore, this role of dynamin as an endocytic GTPase can be inferred from enzymatic activity is markedly increased through association the sequence analyses of the two shibire alleles, shits1 and shits2, with microtubules, acidic phospholipids, and certain regulatory which occur within or near the GTP-binding motif and render proteins that contain Src homology 3 (SH3) domains. From the protein nonfunctional at the restrictive temperature (8). functional, genetic, and cellular manipulations, it is now gener- Similar mutations in dynamin overexpressed in mammalian ally accepted that dynamin participates in the endocytic uptake cells inhibit receptor-mediated endocytosis and produce the of receptors, associated ligands, and plasma membrane following shits phenotype (10–13). Thus, the extensive degree of struc- an exocytic event. These observations have confirmed at least one tural similarity between dynamin and the shibire gene product function of dynamin that was predicted from seminal studies on suggests that they share functional homology and, as discussed a pleiotropic mutant, shibirets (shits)inDrosophila melanogaster. below, substantiates recent experiments testing the involve- Of equal interest is the finding that there are multiple dynamin ment of dynamin in receptor-mediated endocytosis. gene products, including two that are expressed in a tissue- specific manner, and they share marked homology with a larger Identification of Novel Dynamin-Encoding Genes family of distinct but related proteins. Therefore, it is attractive to speculate that the different dynamins may participate in Because dynamin and its encoding cDNA were both originally related cellular functions, such as distinct endocytic processes isolated from mammalian brain, it was thought to be a and even secretion. In turn, dynamin could play an important neuron-specific protein. Early studies using Western and role in cell growth, cell spreading, and neurite outgrowth. The Northern blot analysis appeared to confirm this prediction purpose of this review is to enumerate on the expansive dynamin (14). Subsequent studies using antibodies and cDNA probes to literature and to discuss the nomenclature, expression, and the enzymatic head domain of dynamin suggested that a highly putative functions of this growing and interesting family of related protein may be ubiquitous in distribution (15). There- proteins. fore, several laboratories initiated a search for additional dynamin-encoding genes that could be expressed in other tissues. Our laboratory (15) and Sontag et al. (16) indepen- Early Insights from the Drosophila melanogaster Mutant, dently isolated and characterized a novel dynamin-encoding shibirets (shits) cDNA that is ubiquitously expressed in all rat tissues examined. Sequence analyses revealed that this gene encodes for a shits flies were initially isolated as temperature-sensitive par- protein of 868 aa with a calculated molecular mass of 98.2 kDa alytic mutants (1). The temperature-dependent paralysis that and is 79% identical at the protein level to the previously occurs in these flies results from a depletion of neurotrans- described rat brain dynamin. At the same time, Nakata et al. mitter-containing vesicles at nerve terminals (2). Ultrastruc- (17) isolated an additional dynamin cDNA from rat testis. The tural studies have revealed that this reduction in the number complete open reading frame encoded for a novel protein of of synaptic vesicles (SVs) is caused by an impairment in vesicle 848 aa, which is approximately 80% identical to the two other membrane recycling following exocytosis, resulting in an accu- dynamin isoforms. Northern blot analysis and in situ hybrid- mulation of ‘‘collared pits’’ at the presynaptic plasma membrane ization experiments had showed that this gene is expressed (refs. 3–5; Fig. 1 a–c). Interestingly, these invaginations accumu- exclusively in Sertoli cells of the testis, although a recent study late in a number of other cell types in these flies, indicating a by Cook et al. (18) has demonstrated that this gene is also general defect in endocytosis (refs. 5 and 6; Fig. 1d). expressed in the brain and the lung. The degree of identity Shortly after the initial purification of dynamin from bovine between the rat brain-specific dynamin and the other dynamin brain, a cDNA encoding the full rat brain dynamin was isolated family members is exceptionally high at the amino terminus, by Obar et al. (7) using an anti-dynamin polyclonal antibody. which contains the tripartite GTP-binding motif (Fig. 2) and Subsequently, sequence analysis of the D. melanogaster shibire is highly conserved with the shibire gene product. In addition, dynamins also contain a pleckstrin homology motif and a The publication costs of this article were defrayed in part by page charge proline-rich carboxyl-terminal tail. To distinguish among the payment. This article must therefore be hereby marked ‘‘advertisement’’ in different dynamin isoforms, we will follow the nomenclature accordance with 18 U.S.C. §1734 solely to indicate this fact. Copyright q 1997 by THE NATIONAL ACADEMY OF SCIENCES OF THE USA Abbreviations: SV, synaptic vesicle; CME, clathrin-mediated endocy- 0027-8424y97y94377-8$2.00y0 tosis; FPE, fluid phase endocytosis; Mt, microtubule. PNAS is available online at http:yywww.pnas.org. *To whom correspondence should be addressed. 377 Downloaded by guest on September 25, 2021 378 Review: Urrutia et al. Proc. Natl. Acad. Sci. USA 94 (1997) FIG. 2. Domain structure of the dynamin family. The products of three distinct mammalian genes have been characterized and give rise to multiple proteins that are generated by alternative splicing of the mRNA. DynI is expressed in neuronal tissue, DynII is expressed in all tissues, and DynIII is expressed in the brain, lung, and testis. Dynamin isoform nomenclature makes use of the alternative splice sites; thus the 96-kDa form of DynI is either DynIaa or DynIba, while the 94-kDa form is DynIab or DynIbb. [Reproduced with permission from Rob- inson et al. (19) (Copyright 1994, Elsevier Science).] Multiple Dynamins for Distinct Endocytic Pathways As described above, there are at least three different dynamin genes with several alternatively spliced forms (Fig. 2). This poses the question as to why are there so many dynamins and whether they perform unique or redundant cellular functions. Because DynII is expressed in all cells and tissues that have FIG. 1. Endocytosis in neurons and epithelial cells is structurally altered in the Drosophila mutant shits.(aand b) Electron micrographs been examined (15, 16), it is attractive to predict that it of a typical coxal synapse of a shits flyat198C (permissive tempera- participates in a ubiquitous process such as clathrin-mediated ture), which is characterized by numerous SVs, mitochondria (M), and endocytosis (CME). At present, the evidence implicating a a presynaptic dense body (DB). (b) A similar synapse at the restrictive dynamin in CME is extensive. Morphological studies of epi- temperature of 298C. Note the loss of SVs and the appearance of thelial tissues from shits flies show an accumulation of clathrin- several small invaginations of the plasma membrane, which lack coated pits (refs. 5 and 6; Fig. 1d). This observation is clathrin but possess an electron-dense ring or collar around their necks complemented by recent studies in cultured mammalian cells (arrowheads). (c) A higher magnification of a synapse containing collared pits at 298C. (d) In contrast to neuronal cells, long labyrinthine transfected with various dynamin mutations (10–13). Al- channels are formed in the cortical region of a shits garland cell at the though these later experiments transfected neuronal DynI into restrictive temperature that lack collars. Cells have been impregnated epithelial cells, the effects on CME and cellular morphology with tannic acid to show that these structures (arrows) are continuous were dramatic and convincing. Endocytic uptake of labeled with the plasma membrane and end with a clathrin-coated pit (ar- transferrin in these cells was markedly reduced, and long rowheads). Few discrete coated vesicles are seen. [a–c were repro- tubular endocytic structures (Fig. 3a), reminiscent of those duced with permission from Koenig and Ikeda (4) (Copyright 1989, seen in shits flies (Fig. 1), were present. In many instances, d Soc. Neurosci.); and was reproduced with permission from Kosaka clathrin cages appeared
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