Spectrin and ankyrin-based pathways: Metazoan inventions for integrating cells into tissues

The spectrin-based membrane skeleton of the humble mammalian erythrocyte ha s provided biologists with a set of interacting proteins with diverse roles in organization and survival of cells in metazoan organisms. This review d eals with the molecular physiology of spectrin, ankyrin, which links spectr in to the anion exchanger, and two spectrin-associated proteins that promot e spectrin interactions with actin: adducin and protein 4.1. The lack of es sential functions for these proteins in generic cells grown in culture and the absence of their genes in the yeast genome have, until recently, limite d advances in understanding their roles outside of erythrocytes. However, c ompletion of the genomes of simple metazoans and application of homologous recombination in mice now are providing the first glimpses of the full scop e of physiological roles for spectrin, ankyrin, and their associated protei ns. These functions now include targeting of ion channels and cell adhesion molecules to specialized compartments within the plasma membrane and endop lasmic reticulum of striated muscle and the nervous system, mechanical stab ilization at the tissue level based on transcellular protein assemblies, pa rticipation in epithelial morphogenesis, and orientation of mitotic spindle s in asymmetric cell divisions. These studies, in addition to stretching th e erythrocyte paradigm beyond recognition, also are revealing novel cellula r pathways essential for metazoan life. Examples are ankyrin-dependent targ eting of proteins to excitable membrane domains in the plasma membrane and the Ca2+ homeostasis compartment of the endoplasmic reticulum. Exciting que stions 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.