Review article

The role of serine/threonine protein phosphatases in exocytosis

Alistair T. R. SIM, Monique L. BALDWIN, John A. P. ROSTAS, Jeff HOLST, Russell I. LUDOWYKE

Abstract

Modulation of exocytosis is integral to the regulation of cellular signalling, and a variety of disorders (such as epilepsy, hypertension, diabetes and asthma) are closely associated with pathological modulation of exocytosis. Emerging evidence points to protein phosphatases as key regulators of exocytosis in many cells and, therefore, as potential targets for the design of novel therapies to treat these diseases. Diverse yet exquisite regulatory mechanisms have evolved to direct the specificity of these enzymes in controlling particular cell processes, and functionally driven studies have demonstrated differential regulation of exocytosis by individual protein phosphatases. This Review discusses the evidence for the regulation of exocytosis by protein phosphatases in three major secretory systems, (1) mast cells, in which the regulation of exocytosis of inflammatory mediators plays a major role in the respiratory response to antigens, (2) insulin-secreting cells in which regulation of exocytosis is essential for metabolic control, and (3) neurons, in which regulation of exocytosis is perhaps the most complex and is essential for effective neurotransmission.

  • β-cell
  • exocytosis
  • mast cell
  • neuron
  • phosphatase
  • signal transduction

Footnotes

  • 2 Present address: Proteome Systems Ltd, 1/35-41 Waterloo Road, North Ryde, NSW 2113, Sydney, Australia.

  • Abbreviations used: SNARE, soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor; SNAP, soluble N-ethylmaleimide-sensitive adaptor protein; SM, Sec1Munc18-like; PP1 etc., protein phosphatase 1 etc; PPP, phosphoprotein phosphatase; PPM, protein phosphatase M (Mg2+-dependent phosphatases); PKA, protein kinase A; AKAP, A kinase anchoring protein; CG-NAP, centrosome-and-Golgi-localized protein kinase N-associated protein; NMDA, N-methyl-d-aspartate; LTP, long-term potentiation; PKC, protein kinase C; MLCK, myosin light chain kinase; WD repeat, tryptophan-aspartic acid repeat; SV40, simian virus 40; CaNB, calcineurin regulatory subunit B; DSCR1, Down's syndrome candidate region; JNK, c-Jun N-terminal kinase; TPR, tetratricopeptide repeat; ILK1, integrin-linked kinase 1; ILKAP, ILK1-associated phosphatase; MKK, mitogen-activated protein (MAP) kinase kinase; MKKK, MAP kinase kinase kinase; TGF-β, transforming growth factor-β; I1, inhibitor-1; I2, inhibitor-2; PHAP, putative histocompatibility leucocyte antigens class II-associated protein; CsA, cyclosporin A; KHC, kinesin heavy chain; 4AP, 4-aminopyridine.