Spectrin and Ankyrin-Based Pathways: Metazoan Inventions for Integrating Cells Into Tissues

Abstract

The spectrin-based membrane skeleton of the humble mammalian erythrocyte has provided biologists with a set of interacting proteins with diverse roles in organization and survival of cells in metazoan organisms. This review deals with the molecular physiology of spectrin, ankyrin, which links spectrin to the anion exchanger, and two spectrin-associated proteins that promote spectrin interactions with actin: adducin and protein 4.1. The lack of essential functions for these proteins in generic cells grown in culture and the absence of their genes in the yeast genome have, until recently, limited advances in understanding their roles outside of erythrocytes. However, completion of the genomes of simple metazoans and application of homologous recombination in mice now are providing the first glimpses of the full scope of physiological roles for spectrin, ankyrin, and their associated proteins. These functions now include targeting of ion channels and cell adhesion molecules to specialized compartments within the plasma membrane and endoplasmic reticulum of striated muscle and the nervous system, mechanical stabilization at the tissue level based on transcellular protein assemblies, participation in epithelial morphogenesis, and orientation of mitotic spindles in asymmetric cell divisions. These studies, in addition to stretching the erythrocyte paradigm beyond recognition, also are revealing novel cellular pathways essential for metazoan life. Examples are ankyrin-dependent targeting of proteins to excitable membrane domains in the plasma membrane and the Ca(2+) homeostasis compartment of the endoplasmic reticulum. Exciting questions for the future relate to the molecular basis for these pathways and their roles in a clinical context, either as the basis for disease or more positively as therapeutic targets.

Basolateral junctions are sufficient to suppress epithelial invasion during Drosophila oogenesis

“…The Fas2 tumor invasion and blocked BC migration phenotypes indicate that Fas2 is both necessary and sufficient to inhibit invasion, and that its pattern of expression predicts epithelial invasion. (Goodman et al, 1997); Dlg-4.1 (Lue et al, 1996); Nrg-Ank (Hortsch et al, 1998); 4.1-Spec/Act and Ank-Spec/Act (Bennett and Baines, 2001). Scrib, which is also localized to BLJ, is not shown since we found that its loss does not cause invasion as defined in this work.…”

Critical interactions between TGF-β signaling/ELF, and E-cadherin/β-catenin mediated tumor suppression

“…Several means of silencing E-cadherin gene expression in gastric carcinoma have been observed, including methylation of the E-cadherin promoter, E-cadherin gene truncation mutations and loss of heterozygosity of the E-cadherin locus (Rosivatz et al, 2002;Brooks-Wilson et al, 2004;Scartozzi et al, 2004;Yang et al, 2004). However, these mechanisms account for only a portion of the E-cadherin-negative gastric carcinomas.…”

Apparent structural differences at the tetramerization region of erythroid and nonerythroid beta spectrin as discriminated by phage displayed scFvs

“…Thus, in a mixture of aI, aII, bI, and bII, the concentration or the level of (aII/bI) 2 would decrease slightly in the presence of a specific bI-interactor (e.g., a cellular protein), as the interactor competes with aII for bI and may reduce the amount of (aII/bI) 2 formation. However, the concentration of (aII/bII) 2 should not change, as bI-interactor does not compete with aII for bII. Similarly, cellular proteins with structural features similar to scFv F11 may affect the tetramer concentration of (aII/bII) 2 , but not (aII/bI) 2 .…”

“…1 Spectrin and other proteins such as actin, ankyrin, and protein 4.1 form a cytoskeletal network. 2,3 The most common and well studied spectrin isoforms are erythroid aIand bI-spectrin, and nonerythroid aII-and bII-spectrin. 1 It is generally accepted that aI-, aII-, bI-, and bII-spectrin are all expressed within neurons, [4][5][6][7][8] with aI-and bI-spectrin found in neuronal cell bodies, dendrites, and postsynaptic terminals of neurons, 9 whereas aII-and bII-spectrin are found in the axon and presynaptic termini.…”