New insights into potential functions for the protein 4.1superfamily of proteins in kidney epithelium Page: 3 of 32
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Protein 4.1 in kidney physio-pathology
these cells (41-43), and the key role played by the cytoskeleton in targeting and positioning membrane proteins in these cells (7,
138-144). Importantly, while such protein complexes exist as soluble cytoplasmic scaffolds in non-confluent cells, they are
targeted to cell-cell contact regions of the membrane in confluent cells, namely the lateral domain in the kidney epithelium, under
the control of cell adhesion molecules (145-150). The apical membrane of the kidney epithelium is also divided into
microdomains in which proteins segregate, also through interactions with the cytoskeleton (151-158). Those general concepts are
likely to be applicable to most epithelia.
4.1. Renal 4.1 proteins
We have recently established that three members of the protein 4.1 family, i.e 4.1B, 4.iR and 4.iN, are expressed in
mouse kidney (71). We have extensively characterized the kidney-specific splicing events in each protein 4.1 gene and the
consequences of these splicing events on the structure of kidney protein 4.1 isoforms. Thus, compared to the full length proteins
displayed in Figure 1, kidney 4.1B and kidney 4.iR both lack the U1 region. In addition, all three proteins lack small regions at
the boundary of the U2 region and the SAB domain. Moreover, kidney 4.1B lacks a small N-terminal peptide in the U3 region
and kidney 4.iN lacks most of the U3 region. Lastly, kidney 4.1B bears a truncation of the very end of the C-terminal domain
(66, 71, 88). The absence of defined domains in renal 4.1 proteins likely confers upon their structure specific features that meet
functional requirements in the context of the kidney epithelium. Indeed, we and others have gathered evidence for some of these
kidney-specific splicing events either impairing or facilitating interactions of protein 4.1 isoforms with specific binding partners.
For example, the major isoform of kidney 4.iR lacks a small peptide encoded by exon 16. Since this peptide contains a spectrin-
binding motif (93, 129, 159, 160) and a nuclear localization signal (32, 33, 131, 161), we predict that this kidney 4.iR isoform
will interact weakly with spectrin and will show low level of nuclear localization. A smaller pool of kidney 4.iR containing this
peptide is expected to be targeted to unique cellular compartments and/or to interact with unique binding partners. In a similar
fashion, the absence of the exon 21-encoded peptide in kidney 4.1B is expected to impair kidney 4.1B interaction with proteins
such as NuMA (36, 42). We are currently gathering evidence for the U1 region modulating the binding affinity of protein 4.1
FERM domains for selected transmembrane or membrane-associated proteins (our unpublished data). We also anticipate that
inclusion of exon 17B-encoded peptide in the major kidney 4.iR isoform and exclusion of exon 17D-encoded peptide in kidney
4.iN (those peptides accounting for most of the U3 region in these two 4.1 proteins, respectively) may either promote or inhibit
4.iR and 4.iN interaction with selected renal binding partners.
An intriguing feature of renal 4.1 proteins is their mutually exclusive expression along the nephron: 4.1B is primarily
expressed in the proximal convoluted tubule (PCT) and the glomerulus, while 4.1R is detected in the thick ascending limb (TAL)
of the loop of Henle, and 4.iN in the thin limb of the loop of Henle, the distal convoluted tubule (DCT) and all regions of the
collecting duct (71, 72). At the cellular level, all 4.1 proteins are detected in the basolateral region of the kidney epithelium.
Given the extensive knowledge of transport functions dedicated to each segment of the nephron, these observations strongly
suggest that each 4.1 protein is likely involved in the organization of region-specific protein scaffolds and therefore likely plays
unique functions in kidney.
Interestingly, 4.iR null mice display not only the expected hematopoietic phenotype (chronic hemolytic anemia,
splenomegaly, spherocytosis and reticulocytosis; (162)) but also neuro-behavioral deficits, likely resulting from the lack of 4.iR
expression in cerebellum, dentate gyrus and hippocampus (70), and a renal phenotype (our unpublished data). Indeed, 4.iR null
mice present with a slight urine acidification and alterations in Na/K balance upon water deprivation. More recently, we have
reported that 4.iR null red blood cells display hyperactivity of the sodium-proton exchanger NHE1 (163), of the "Gardos
channel" calcium-gated potassium channel (163, 164) and of a potassium-chloride co-transporter (163). Terada et al. have also
suggested an interaction between 4.1B and the sodium bicarbonate co-transporter NBC1 in the PCT based on electron
microscopy analysis of kidney sections showing co-localization of the two proteins (72). Taken together, these recent findings
provide us with interesting leads as for identifying additional ion transporters interacting with 4.1 proteins in the kidney
4.2. Renal ezrin
A member of the protein 4.1 superfamily, ezrin, is expressed at high levels at the apical pole of epithelia including
kidney (158) (Figure 4). Up-regulation of ezrin expression is a hallmark of major kidney diseases such as polycystic kidney
disease (165) and nephrogenic diabetes insipidus (166). Ezrin, in association with PDZ domain containing protein sodium-proton
exchanger regulatory factor 2 (NHERF-2), bridges the cytoskeleton and the integral membrane protein podocalyxin in podocytes
(167), disorganization of this link leading to a dramatic loss in glomerular foot processes (168). A NHERF-2/podocalyxin
complex has also been recently characterized in the apical region of MDCK cells undergoing polarization (169). In a similar
fashion, in concert with PDZ domain-containing protein NHERF-1, ezrin has been shown to regulate sodium and phosphate
reabsorption and proton secretion at the apical pole of the proximal convoluted tubule through its interaction with the
sodium/phosphate co-transporter Npt2 and the sodium proton exchanger NHE3, respectively (170, 171). Thus, ezrin binds to the
cytoplasmic domain of NHE3 but recruits also adapter and signaling molecules, i.e. NHERF-1 and cyclic AMP-dependent
protein kinase (PKA) (172-174). Recruitment of PKA in the vicinity of NHE3 represents a key event in the regulation of NHE3
exchanger activity. Alterations in ezrin expression and PKA signaling have been observed in polycystic kidney disease (165).
Co-staining of mouse kidney with an anti 4.1B antibody and either an anti-ezrin or an anti-NHERF-1 antibody
illustrates the mutually exclusive expression of renal 4.1 proteins and ezrin or NHERF-1 at the basolateral and apical pole of the
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Calinisan, Venice; Gravem, Dana; Chen, Ray Ping-Hsu; Brittin,Sachi; Mohandas, Narla; Lecomte, Marie-Christine et al. New insights into potential functions for the protein 4.1superfamily of proteins in kidney epithelium, article, June 17, 2005; Berkeley, California. (digital.library.unt.edu/ark:/67531/metadc892527/m1/3/: accessed October 15, 2018), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT Libraries Government Documents Department.