Diakowski, W., Grzybek, M. & Sikorski, A.F. Protein 4.1, a component of the erythrocyte membrane skeleton and its related homologue proteins forming the protein 4.1/FERM superfamily. Folia Histochem. Cytobiol. 44, 231-248

Faculty of Biotechnology, University of Wrocław, Wrocław, Poland.
Folia Histochemica et Cytobiologica (Impact Factor: 1). 02/2006; 44(4):231-48.
Source: PubMed

ABSTRACT The review is focused on the domain structure and function of protein 4.1, one of the proteins belonging to the membrane skeleton. The protein 4.1 of the red blood cells (4.1R) is a multifunctional protein that localizes to the membrane skeleton and stabilizes erythrocyte shape and membrane mechanical properties, such as deformability and stability, via lateral interactions with spectrin, actin, glycophorin C and protein p55. Protein 4.1 binding is modulated through the action of kinases and/or calmodulin-Ca2+. Non-erythroid cells express the 4.1R homologues: 4.1G (general type), 4.1B (brain type), and 4.1N (neuron type), and the whole group belongs to the protein 4.1 superfamily, which is characterized by the presence of a highly conserved FERM domain at the N-terminus of the molecule. Proteins 4.1R, 4.1G, 4.1N and 4.1B are encoded by different genes. Most of the 4.1 superfamily proteins also contain an actin-binding domain. To date, more than 40 members have been identified. They can be divided into five groups: protein 4.1 molecules, ERM proteins, talin-related molecules, protein tyrosine phosphatase (PTPH) proteins and NBL4 proteins. We have focused our attention on the main, well known representatives of 4.1 superfamily and tried to choose the proteins which are close to 4.1R or which have distinct functions. 4.1 family proteins are not just linkers between the plasma membrane and membrane skeleton; they also play an important role in various processes. Some, such as focal adhesion kinase (FAK), non-receptor tyrosine kinase that localizes to focal adhesions in adherent cells, play the role in cell adhesion. The other members control or take part in tumor suppression, regulation of cell cycle progression, inhibition of cell proliferation, downstream signaling of the glutamate receptors, and establishment of cell polarity; some are also involved in cell proliferation, cell motility, and/or cell-to-cell communication.

Download full-text


Available from: Aleksander F. Sikorski, Aug 27, 2015
  • Source
    • "However, its theoretical molecular weight is ∼100 kDa. This discrepancy results from the unstructured state of the HP region [23] "
    [Show abstract] [Hide abstract]
    ABSTRACT: Membrane skeletal protein 4.1R is the prototypical member of a family of four highly paralogous proteins that include 4.1G, 4.1N, and 4.1B. Two isoforms of 4.1R (4.1R(135) and 4.1R(80)), as well as 4.1G, are expressed in erythroblasts during terminal differentiation, but only 4.1R(80) is present in mature erythrocytes. One goal in the field is to better understand the complex regulation of cell type and isoform-specific expression of 4.1 proteins. To start answering these questions, we are studying in depth the important functions of 4.1 proteins in the organization and function of the membrane skeleton in erythrocytes. We have previously reported that the binding profiles of 4.1R(80) and 4.1R(135) to membrane proteins and calmodulin are very different despite the similar structure of the membrane-binding domain of 4.1G and 4.1R(135). We have accumulated evidence for those differences being caused by the N-terminal 209 amino acids headpiece region (HP). Interestingly, the HP region is an unstructured domain. Here we present an overview of the differences and similarities between 4.1 isoforms and paralogs. We also discuss the biological significance of unstructured domains.
    International Journal of Cell Biology 08/2011; 2011:943272. DOI:10.1155/2011/943272
  • Source
    • "The proteins of the ERM family have structural resemblances but are still distinct . However, they all share the FERM (band 4.1, ezrin, radixin, and moesin) domain, an N-terminal domain highly conserved in this band 4.1 subclass (Chishti et al., 1998; Bretscher et al., 2002), which includes talin and FAK, both of which are involved in cell motility regulation (Diakowski et al., 2006). We do not know whether the BRCT domains of BRCA1 interact with the FERM domain in these proteins, but note that we did not detect other FERM domain–containing proteins in our ligand overlay experiments. "
    [Show abstract] [Hide abstract]
    ABSTRACT: BRCA1 C-terminal (BRCT) domains in BRCA1 are essential for tumor suppressor function, though the underlying mechanisms remain unclear. We identified ezrin, radixin, and moesin as BRCA1 BRCT domain-interacting proteins. Ezrin-radixin-moesin (ERM) and F-actin colocalized with BRCA1 at the plasma membrane (PM) of cancer cells, especially at leading edges and focal adhesion sites. In stably expressing cancer cells, high levels of enhanced green fluorescent protein (EGFP)-BRCA1(1634-1863) acted as a dominant-negative factor, displacing endogenous BRCA1 from the PM. This led to delayed cell spreading, increased spontaneous motility, and irregular monolayer wound healing. MCF-7 cells (intact BRCA1) showed lower motility than HCC1937 cells (truncated BRCA1), but expression of EGFP-BRCA1(1634-1863) in MCF-7 increased motility. Conversely, full-length BRCA1 expression in HCC1937 decreased motility but only if the protein retained ubiquitin ligase activity. We conclude that full-length BRCA1 is important for complete tumor suppressor activity via interaction of its BRCT domains with ERM at the PM, controlling spreading and motility of cancer cells via ubiquitin ligase activity.
    The Journal of Cell Biology 02/2011; 192(3):497-512. DOI:10.1083/jcb.201004136 · 9.69 Impact Factor
  • Source
    • "It can bind SHP-2 (Yamasaki et al. 2001) and it may compete with SLP-76 for binding to Grb2 and Gads (Yamasaki et al. 2003). Other molecules that may mediate inhibitory signaling are the adapter SLAP (Src-like adapter protein) (Myers et al. 2006), the tyrosine phosphatase SHP-1 (Lorenz 2009) and 4.1R (Diakowski et al. 2006). 4.1R binds LAT directly and is thought to prevent LAT phosphorylation by ZAP-70 (Kang et al. 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The adapter molecule LAT is a nucleating site for multiprotein signaling complexes that are vital for the function and differentiation of T cells. Extensive investigation of LAT in multiple experimental systems has led to an integrated understanding of the formation, composition, regulation, dynamic movement, and function of LAT-nucleated signaling complexes. This review discusses interactions of signaling molecules that bind directly or indirectly to LAT and the role of cooperativity in stabilizing LAT-nucleated signaling complexes. In addition, it focuses on how imaging studies visualize signaling assemblies as signaling clusters and demonstrate their dynamic nature and cellular fate. Finally, this review explores the function of LAT based on the interpretation of mouse models using various LAT mutants.
    Cold Spring Harbor perspectives in biology 08/2010; 2(8):a005512. DOI:10.1101/cshperspect.a005512 · 8.23 Impact Factor
Show more