Professor, Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University
Chair, Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University
Academic Advisory Committee, ISEF Foundation
Academic Advisory Committee, Gazit-Globe Foundation
Pathobiology of Secretory Granule Packaging and Growth
Unit Granule formation: The classical model of secretory granule formation holds that proteins are transported from the RER to the Golgi zone where they can undergo post-transitional modification. They are then packaged for secretion by concentration within membrane-bound condensing vacuoles. The transportation of secretory proteins occurs in a vectorial way. The newly synthesized proteins in the RER are moved, probably via a vesicular transport, to the proximal side of the Golgi cisternae, the cis Golgi side. While moving through the Golgi cisternae the proteins undergo many modifications; most of the steps of which have not yet been resolved. The processed proteins are packed into vesicles that bud off the Golgi cisternae. The elucidation of this sequence of protein synthesis, packaging and secretion constitutes a major contribution to cell biology. It is well documented that granules in various cellular systems increase in size as time passes. For example, after degranulation is induced in either mast cells or mouse pancreatic acinar cells, granules start to accumulate. If the cell is not re-sensitized, the granule size distribution becomes broader and the mean granule size is increased.
We have demonstrated that the unit granule volume is conserved; indicating that the granule size increase is probably due to homotypic fusion. The mechanism of polymerization is theoretically and experimentally investigated by us. It is found that two major mechanisms may lead to polymerization. The first one is defined as unit addition mechanism, while the second one is defined as a random addition process. We have demonstrated that the pancreatic acinar cell and mast cell granule size distribution is better fitted to the unit addition model rather than the random addition model. The Chediak-Higashi syndrome is an example of a random mechanism of granule growth.
Publications
Hammel I, Shoichetman T, Amihai D, Galli SJ, Skutelsky E. Localization of anionic constituents in mast cell granules of brachymorphic (bm/bm) mice by using avidin-conjugated colloidal gold. Cell Tissue Res. 2010; 339:561-70.
Nitzany E, Hammel I, Meilijson I. Quantal basis of vesicle growth and information content, a unified approach. J Theor Biol. 2010 ;266:202-9.
Hammel I, Lagunoff D, Galli SJ. Regulation of secretory granule size by the precise generation and fusion of unit granules. J Cell Mol Med. 2010; 14:1904-16
Gorzalczany Y, Gilad Y, Amihai D, Hammel I, Sagi-Eisenberg R, Merimsky O, Combining an EGFR directed tyrosine kinase inhibitor with autophagy-inducing drugs; A beneficial strategy to combat non-small cell lung cancer. Cancer Letters 2011; 310:207-15.
Hammel I, Wang CC, Hong W, Amihai D. VAMP8/Endobrevin is a critical factor for the homotypic granule growth in pancreatic acinar cells. Cell Tissue Res. 2012; 348:485-490
Hammel I, Meilijson I. Function suggests nano-structure: electrophysiology supports that granule membranes play dice. J R Soc Interface. 2012; 9:2516-26.
Hammel I, Meilijson I. Function suggests nano-structure: towards a unified theory for secretion rate, a statistical mechanics approach. J R Soc Interface. 2013, 10, 20130640.
Kepelová-Dror M, Hammel I, Meilijson I. Statistical analysis of the quantal basis of secretory granule formation. Microsc Res Tech. 2014;77:1-10.
Azouz NP, Zur N, EferganA, Ohbayashi N, Fukuda M, Amihai D, Hammel I, Rothenberg ME, Sagi-Eisenberg R. Rab5 is a novel regulator of mast cell secretory granules: impact on size, cargo and exocytosis. J Immunol. 2014;192:4043-53.
Chapters
Trachtenberg S, Hammel I. Determining the persistence length of biopolymers and rod-like macromolecular assemblies from electron microscope images and deriving some of their mechanical properties. In: Microscopy: Science, Technology, Applications and Education, A. Méndez-Vilas and J. Díaz (Eds.) Microscopy book Series. Number 4, Vol. 3, pp. 1690-1695, 2010.
Hammel I, Meilijson I. Granule size distribution suggests mechanism: the case for granule growth and elimination as a fusion nano-machine. In: NanoCellBiology: Multimodal Imaging in Biology & Medicine, Pan Sanford Publishing Pte. Ltd. Editors: Jena, B.P., Taatjes, D.J. 2013, In press.
Invited editorials
Hammel I, Lagunoff D, Galli SJ. Regulation of secretory granule size by the precise generation and fusion of unit granules. J. Cell. Mol. Med. 2010:14:1904-16
Hammel I, Meilijson I. The stealthy nano-machine behind mast cell granule size distribution. Mol Immunol. 2014. pii: S0161-5890(14)00032-7. doi: 10.1016/ j.molimm.2014.02.005 [Epub ahead of print]
Grants
2014-2017 Binational Science Foundation (Co-PI, Ronit Sagi-Eisenberg)
