Research Interests:
Recombinatorial Diversity of Spectrin/Ankyrin Affinities
Our lab studies how the cytoskeletal protein spectrin, and its cohort
ankyrin, help to organize cellular architecture and function. One of
the hallmark features of the eukaryotic epithelial cell is its ability
to organize the cellular milieu in a polarized fashion, allowing for
the establishment of basal, lateral and apical domains. Polarization
gives cells the capacity to perform specialized functions such as the
attachment to basal membranes, cell-cell contact, formation of tight
junctions, directional ion transport, sensory perception, signal transduction,
targeted secretion and endocytosis. Besides epithelial cells many other
cell types, such as neurons, photoreceptors and muscle, require an organized
distribution of protein for proper function. Even seemingly non-polar
cells such as erythrocytes and lymphocytes have been shown to exhibit
polarity within lipid membrane raft micro-domains that also may be stabilized
by an underlying spectrin/ankyrin cytoskeleton.
Clearly, improper targeting or maintenance of the cellular architecture
can compromise cell function, as demonstrated in patients with Cystic
Fibrosis where a single point mutation in the transmembrane conductance
regulatory gene has been shown to prevent proper delivery and stabilization
of this protein at the plasma membrane.
How the many different cell types establish and maintain a polarized
distribution for so many diverse proteins is of considerable dispute.Certainly
studies have shown that spectrin, through its association with ankyrin,
has the ability to bind and stabilize several proteins to specific functional
domains within cells. First identified in erythrocytes, spectrin, composed
of two large anti-parallel alpha and beta chains in a tetrameric formation,
and ankyrin, a tripartite molecule with 24 33-amino acids repeats, have
been shown to bind and stabilize the anion exchanger molecule to the
red cell membrane. Subsequently, an additional alpha and 4 additional
beta spectrin genes have been discovered, each with putative splice
variants. Equivalently, two additional ankyrin genes are now known,
also with multiple spliced isoforms, and it has been shown that the
ankyrin repeats act like a molecular Velcro for binding many other proteins.
The growing list for molecules tethered by spectrin and ankyrin now
encompasses a small cadre of proteins including the Na-K-ATPas and H,K-ATPase
in epithelial cells (1), CD45 and protein Kinase C in lymphocytes (2),
L1 CAMs, IP3 and Ryanodine receptors in Brain, and Sodium Channel clustering
in axons (3,4).
Impressively, the spectrin ankyrin complex may present the recombinatorial
potential necessary to accommodate many more as yet unidentified protein
interactions and subsequent cellular distributions. Little is known
about the preference for the different spectrin genes to form mixed
hetero-tetramers bestowing diversified binding characteristics for ankyrin
or other tethered proteins. Our lab has been looking at these interactions
with an interest in their clinical significances.
Stabach PR, Morrow JS. Identification
and Characterization of Beta V Spectrin, a Mammalian Ortholog of Drosophila
Beta H Spectrin. J Biol Chem. 2000 Jul 14;275(28):21385-95.
Selected Publications:
1. Street M, Marsh SJ, Stabach PR, Morrow JS, Brown DA, Buckley
NJ. Stimulation
of G{alpha}q-coupled M1 muscarinic receptor causes reversible spectrin
redistribution mediated by PLC, PKC and ROCK. J Cell Sci. 2006 Apr
15;119(Pt 8):1528-36. Epub 2006 Mar 21. PMID: 16551696 [PubMed - indexed
for MEDLINE].
2. Stankewich MC, Stabach PR, Morrow JS. Human
Sec31B: a family of new mammalian orthologues of yeast Sec31p that associate
with the COPII coat. J Cell Sci. 2006 Mar 1;119(Pt 5):958-69. PMID:
16495487 [PubMed - indexed for MEDLINE].
3. Stabach PR, Thiyagarajan MM, Woodfield GW, Weigel RJ. AP2alpha
alters the transcriptional activity and stability of p53. Oncogene.
2006 Apr 6;25(15):2148-59.PMID: 16288208 [PubMed - indexed for MEDLINE].
4. Wu Y, Stabach P, Michaud M. Madri J. Neutrophils lacking platlet-endothelial
cell adhesion molecule-1 exhibite loss of directionality and motility
in CXCR2-mediated chemotaxis. J Immunology. 2005 Sept 15; 175 (6).
5. Stabach PR, Thiyagarajan MM, Weigel RJ. Expression of ZER6
in ERalpha-positive breast cancer. J Surg Res. 2005 Jun 1;126(1):86-91;
discussion 1-2. PMID: 15916980 [PubMed - indexed for MEDLINE].
6. Berghs S, Aggujaro D, Dirkx R Jr, Maksimova E, Stabach P,
Hermel JM, Zhang JP, Philbrick W, Slepnev V, Ort T, Solimena M. BetaIV
spectrin, a new spectrin localized at axon initial segments and nodes
of ranvier in the central and peripheral nervous system. J Cell Biol.
2000 Nov 27;151(5):985-1002. PMID: 11086001 [PubMed - indexed for MEDLINE].
7. Stabach PR, Morrow JS. Identification
and characterization of beta V spectrin, a mammalian ortholog of Drosophila
beta H spectrin. J Biol Chem. 2000 Jul 14;275(28):21385-95. PMID:
10764729 [PubMed - indexed for MEDLINE].
8. Stankewich MC, Tse WT, Peters LL, Ch'ng Y, John KM, Stabach
PR, Devarajan P, Morrow JS, Lux SE. A widely expressed betaIII spectrin
associated with Golgi and cytoplasmic vesicles. Proc Natl Acad Sci U
S A. 1998 Nov 24;95(24):14158-63. PMID: 9826670 [PubMed - indexed for
MEDLINE].
