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The Cystic Fibrosis Transmembrane Regulator Forms Macromolecular Complexes with PDZ Domain Scaffold Proteins

Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Correspondence and requests for reprints should be addressed to William B. Guggino, Ph.D., Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205. E-mail: wguggino{at}bs.jhmi.edu

	ABSTRACT

TOP ABSTRACT CARBOXYL TERMINUS OF CFTR CAL AND TRAFFICKING OF... NHE-RF, E3KARP, AND CAP70... DYNAMIC INTERACTION AT THE... PDZ DOMAIN OF CFTR... WHAT IS THE FUNCTIONAL... REFERENCES

 
Cystic fibrosis transmembrane regulator (CFTR), an epithelial Cl^– channel defective in cystic fibrosis, is localized at the apical membrane of epithelial cells. CFTR interacts with a number of ion channels (outwardly rectifying chloride channels, epithelial sodium channels, and inwardly rectifying potassium channels), protein kinases A and C, and putative protein phosphatases and ATP transporters. These data suggest that CFTR may exist in macromolecular complexes with these and other scaffolding proteins at the apical membrane. PDZ domain proteins have been shown to localize and cluster CFTR in the Golgi and at the plasma membrane. This review highlights the role of PDZ domain proteins in regulating the trafficking and processing of CFTR.

Key Words: chloride • regulation • trafficking • processing • channel

CFTR, a Cl^– channel that is regulated by phosphorylation and ATP hydrolysis, is localized at the apical membrane in secretory epithelia such as the conducting airways and in the apical and basolateral membrane of the sweat duct. CFTR mediates ion and water transport across the epithelial barrier (1). A number of ion channels work in concert with CFTR. These include outwardly rectifying chloride channels (ORCCs), epithelial sodium channels, and inwardly rectifying potassium channels (see Devidas and Guggino [2] for a review). CFTR is also functionally associated with signal transduction enzymes (1). The functional interaction of CFTR with other proteins suggests that CFTR may be physically associated with these proteins.

Ion channels in neuronal tissues are not diffusely distributed throughout the neurons, but rather are localized and clustered at specialized subcellular site such as presynaptic and postsynaptic membranes. Scaffolding proteins that contain PDZ domains typically bind to the C terminus of ion channels and organize them in three-dimensional complexes at these locations (3). The PDZ domain is a modular protein interaction domain consisting of 80–90 amino acids. It was originally identified in postsynaptic density protein PSD95, Drosophila tumor suppressor Dlg, and epithelial tight junction protein ZO-1 (3). In addition to targeting channels and receptors to the specialized membrane, the action of scaffolding proteins organizes the related signaling molecules into macromolecular complexes. For example, the PDZ protein InaD localizes the transient receptor potential channel to the rhabdomere, and assembles the transient receptor potential channel into a functional protein complex with signal transduction molecules (4).

Many proteins participate in the processing of CFTR from the endoplasmic reticulum to the plasma membrane and in organizing CFTR in the plasma membrane. This review highlights the role of PDZ domain proteins in regulating the trafficking and processing of CFTR.

	CARBOXYL TERMINUS OF CFTR

TOP ABSTRACT CARBOXYL TERMINUS OF CFTR CAL AND TRAFFICKING OF... NHE-RF, E3KARP, AND CAP70... DYNAMIC INTERACTION AT THE... PDZ DOMAIN OF CFTR... WHAT IS THE FUNCTIONAL... REFERENCES

 
The carboxyl terminus of CFTR (Table 1) possesses a motif, (D/E)T(R/K)L, that is conserved across species and belongs to the Type I class of PDZ domain-binding motifs (5). At least three PDZ domain proteins are known to bind to the C-terminal motif of CFTR: the sodium–proton exchange regulatory factor (NHE-RF), CFTR-associated protein-70 (CAP70), and CFTR-associated ligand (CAL) (see below).

	CAL AND TRAFFICKING OF CFTR THROUGH THE GOLGI

TOP ABSTRACT CARBOXYL TERMINUS OF CFTR CAL AND TRAFFICKING OF... NHE-RF, E3KARP, AND CAP70... DYNAMIC INTERACTION AT THE... PDZ DOMAIN OF CFTR... WHAT IS THE FUNCTIONAL... REFERENCES

CAL has a molecular mass of about 50 kD. In addition to a PDZ domain, CAL is predicted to have two coiled-coil domains (Figure 1). CAL is ubiquitously expressed in human tissues, including those that contain CFTR and other ion channels. Two other groups have independently identified CAL proteins, alternately named GOPC and PIST. Yao and coworkers (7) identified a Golgi protein, GOPC (Golgi-associated PDZ- and coiled-coil motif-containing protein), and demonstrated its interaction with the frizzled protein. They suggested a role for GOPC in vesicular transport of frizzled from the Golgi apparatus to the plasma membrane. Neubauer and coworkers (8) identified PIST (TC10-specific interacting protein), a binding partner for the low molecular weight GTPase TC10. They suggested that PIST may function as a scaffolding protein to link TC10 to other signaling mechanisms.

View larger version (24K): [in this window] [in a new window]   Figure 1. CAL binds to CFTR most abundantly within the trans-Golgi network and perhaps within the endoplasmic reticulum. As CFTR trafficks to the plasma membrane (solid arrows), NHE-RF or other scaffolding proteins such as CAP70 and E3KARP may compete for binding to CFTR (dotted arrows). PDZ domain-binding partners in the plasma membrane link CFTR either to itself, forming dimers, or to other proteins in a macromolecular complex (R). NHE-RF can also link CFTR to the cytoskeleton via Ezrin (E).

CFTR functions as a Cl^– channel producing linear, cAMP-activated Cl^– currents (see Devidas and Guggino [2] for a review). Cotransfection of CAL with CFTR reduces CFTR currents and surface expression of CFTR. CAL overexpression reduces surface expression CFTR specifically via its PDZ-binding domain and is without effect on proteins that do not contain a PDZ domain capable of binding CAL. Overall the data suggest that CAL functions to tether CFTR at the TGN and may regulate the transit of CFTR through the Golgi to the plasma membrane. CAL itself does not have any predicted transmembrane domains but tethers CFTR at the TGN via its coiled-coil domains (1).

	NHE-RF, E3KARP, AND CAP70 FORM MACROMOLECULAR COMPLEXES CONTAINING CFTR AT THE PLASMA MEMBRANE

TOP ABSTRACT CARBOXYL TERMINUS OF CFTR CAL AND TRAFFICKING OF... NHE-RF, E3KARP, AND CAP70... DYNAMIC INTERACTION AT THE... PDZ DOMAIN OF CFTR... WHAT IS THE FUNCTIONAL... REFERENCES

 
In contrast to CAL, which plays a major role in the Golgi, other PDZ domain-containing proteins bind to CFTR at the plasma membrane. NHE-RF (also known as ezrin/radixin/moesin-binding phosphoprotein-50, and EBP50) is a 42-kD phosphoprotein containing two PDZ domains that regulates the apical membrane Na⁺/H⁺ exchanger NHE3 (9). In experiments to identify binding partners of NHE-RF, our group determined the peptide-binding sequences for individual NHE-RF PDZ domains, using random peptide display. On the basis of information derived from the consensus binding sequences of the PDZ domains, we found that CFTR is a candidate interacting protein for NHE-RF (10). Subsequent binding studies confirmed that the C terminus of CFTR preferentially binds to NHE-RF, to PDZ1 with the highest affinity (about 48 nM), and to PDZ2 with less affinity (11, 12). E3KARP (NHE3 kinase A regulatory protein) also contains two PDZ domains, and shares about 52% amino acid identity with NHE-RF (13). E3KARP also plays a role in the inhibition of NHE3 by cAMP in renal cell lines. The PDZ-binding domain of CFTR binds to E3KARP, also with high affinity.

Finally, our group, using an affinity column with glutathione S-transferase (GST) fusion protein containing the 15 C-terminal residues of human CFTR as bait, purified CAP70 from mouse kidney extracts. CAP70 contains four PDZ domains, three of which can bind to the CFTR C terminus (14). Thus, a picture regarding the functional relevance of the binding to these proteins of the C-terminal tail of CFTR is emerging.

The regulation of CFTR ion channel activity depends on phosphorylation by kinases in the regulatory (R) domain (1). A developing concept is that the C-terminal PDZ domain of CFTR plays a role in bringing kinases in close contact with CFTR. For example, it has been shown that the Yes-associated protein 65 (YAP65) binds with high affinity to PDZ-2 of NHE-RF (15). Wild-type YAP65 is localized at the apical membrane in airway epithelia whereas a mutant YAP65 protein lacking the EBP50 interaction motif is mislocalized. Thus, the interaction of NHE-RF with YAP65 is critical for apical membrane localization. Moreover, the nonreceptor tyrosine kinase C-Yes is contained within EBP50 protein complexes by association with YAP65. Therefore, PDZ protein sequestration of regulatory kinases in close proximity to CFTR may play a role in signaling cascades involving CFTR, eventually leading to the regulation of ion transport.

E3KARP also organizes CFTR into a macromolecular complex that includes protein kinase A linked to the cytoskeleton. One possible function of this complex is to bring protein kinase A into the vicinity of the R domain of CFTR, facilitating its phosphorylation. In support of this concept is that finding that coexpression of CFTR with E3KARP and ezrin in Xenopus oocytes enhances cAMP-stimulated CFTR Cl^– currents (16).

CFTR and the ß₂-adrenergic receptor (ß₂-AR) can bind to NHE-RF through their PDZ domains (17). A study has shown that ß₂-AR is the major adrenergic receptor isoform expressed in airway epithelia, colocalizes with CFTR at the apical membrane, and, when activated, stimulates CFTR (18). Removal of the PDZ-binding domain of CFTR abolishes both the physical interaction with ß₂-AR and the functional response. Interestingly, assembly of the macromolecular complex is inhibited by protein kinase A–dependent phosphorylation of the R domain of CFTR. The importance of this macromolecular complex may be evident in the disease state. For example, in patients with F508 and other mutations that mistraffic CFTR, disruptions in signal transduction may have effects broader than those predicted simply from the absence of a functioning CFTR Cl^– channel.

It is likely that more than one CFTR molecule is present within a given regulatory macromolecular complex containing signal transduction molecules. As mentioned above, CFTR can bind to more than one PDZ domain of both NHE-RF and CAP70 (12, 14). This raises the following question: can CFTR form a dimer through an interaction with PDZ domain proteins? Two independent reports support this notion. Our group showed that CAP70 is capable of linking CFTR molecules to form dimers. In this dimeric form, CFTR channel activity is enhanced (14). Another study showed that the two PDZ domains of NHE-RF (PDZ1 and PDZ2) can promote CFTR dimerization and increase the probability of open CFTR Cl^– channels in excised membrane patches from a lung submucosal gland–derived epithelial cell line (12). Both studies suggest that not only can CFTR exist as a dimer, stabilized by the multiple PDZ-binding domains of NHERF or CAP70, but also that CFTR functions more efficiently in this dimeric state.

CFTR, as evidenced by enhanced residence time, is more stable in the plasma membrane as part of a macromolecular complex with PDZ domain–containing proteins. To study this, our group conducted pulse–chase studies along with selective cell surface biotinylation to evaluate synthesized wild-type CFTR and CFTR-TRL, the latter missing the PDZ-binding domain. We found that both wild-type and CFTR-TRL were targeted to the apical and basolateral membranes in a nonpolarized fashion and that the PDZ-binding domain is not an apical sorting motif. Surprisingly, the half-life of CFTR-TRL in the apical membrane was reduced from about 24 to 13 hours, but there was no change in the half-life of CFTR in the basolateral membrane (19). We concluded from these and other studies (20, 21) that the PDZ-interacting domain is an apical membrane retention motif (19). These data support the notion that when CFTR is within a macromolecular complex its retention in the plasma membrane is increased.

	DYNAMIC INTERACTION AT THE PDZ-BINDING DOMAIN OF CFTR

TOP ABSTRACT CARBOXYL TERMINUS OF CFTR CAL AND TRAFFICKING OF... NHE-RF, E3KARP, AND CAP70... DYNAMIC INTERACTION AT THE... PDZ DOMAIN OF CFTR... WHAT IS THE FUNCTIONAL... REFERENCES

 
The observations that multiple PDZ domain–containing proteins bind to CFTR raise a question regarding the specificity of binding. To understand how PDZ domain proteins work together in regulating CFTR trafficking and membrane organization, we examined the effect of coexpressing NHE-RF and CAL on CFTR cell surface expression (6). As mentioned above, overexpression of CAL reduces surface expression of CFTR. However, coexpression of NHE-RF with hemagglutinin-tagged CAL counteracts the tendency of CAL to retain CFTR in the Golgi and restores cell surface CFTR expression. Because both CAL and NHE-RF bind to the same PDZ-binding motif at the C terminus of CFTR, we tested whether NHE-RF competes with CAL for the binding to CFTR. We showed that the binding of CAL to CFTR was substantially reduced by the coexpression of NHE-RF.

PDZ-mediated binding to CFTR and subsequent assembly into a complex may depend on several factors. One factor may be the specific location of binding partners within the cell. For example, because CAL is abundant within the Golgi, CFTR would bind readily to CAL (6) at this locale. One the other hand, CAP70 and NHE-RF are located at the plasma membrane and would bind to CFTR there (11, 14). Another factor could be tissue abundance. For example, CAP70 is abundant in kidney and small intestine and thus would be a major binding partner for CFTR in those tissues (14). Finally, as has been shown, phosphorylation of the R domain may also play a role in regulating binding of various PDZ domain proteins to the C terminus of CFTR (18). Clearly, the dynamic regulation of CFTR binding to scaffolding proteins, either at the plasma membrane or at the Golgi apparatus, may determine its organization into multimolecular functional units that contain other regulatory molecules, and perhaps other channels.

	PDZ DOMAIN OF CFTR AND CONDUCTANCE REGULATION

TOP ABSTRACT CARBOXYL TERMINUS OF CFTR CAL AND TRAFFICKING OF... NHE-RF, E3KARP, AND CAP70... DYNAMIC INTERACTION AT THE... PDZ DOMAIN OF CFTR... WHAT IS THE FUNCTIONAL... REFERENCES

 
CFTR regulates the function of several other proteins such as ion channels, transporters, and elements of the immune system (see references 2 and 22–25 for examples). It is likely that CFTR interacts with these other proteins in several ways (26). Evidence has emerged regarding the role of PDZ domain proteins in organizing CFTR into a complex with other proteins. Such a complex may allow CFTR to play a regulatory role beyond its own Cl^– channel function. For example, a splice variant of the Cl^– channel ClC-3 (ClC-3B) is expressed in epithelial cells associated with cystic fibrosis (24). ClC-3B has a C-terminal domain that binds to EBP50 (24) and to CAL (25), similar to CFTR. The interaction with EBP50 enhances the outwardly rectifying Cl^– channel (ORCC) activity generated by ClC-3B. Importantly, when CFTR is coexpressed with ClC-3B and EBP50, ORCC currents generated by ClC-3B can be activated via the protein kinase A–dependent pathway. ORCCs native to airway cells are well known to be regulated by protein kinase A only in the presence of a functional CFTR (27). The interaction of ClC-3B with CAL, similar to CFTR, occurs within the Golgi (25) and may control the processing of both channels simultaneously. Although it is still unclear whether ClC-3B contributes to the well-studied ORCC currents in native tissues, these data do show the importance of macromolecular complex formation in the ability of CFTR to regulate other Cl^– channels.

CFTR also plays a role in regulating HCO₃^– transport in pancreas and other secretory epithelia (28). The Na⁺/HCO₃^– cotransporter (NBC) plays a key role in HCO₃^– secretion (29). Evidence has been provided that NBC-3, which also has a PDZ-binding domain, occurs in a macromolecular complex with EBP50 and CFTR in native pancreas and submandibular and parotid glands (22). Stimulation of CFTR with forskolin inhibits NBC-3 activity, again via the protein kinase A pathway, which depends on CFTR. Importantly, the deletion of the C-terminal PDZ-binding domain of CFTR or NBC-3 abolishes both complex formation and inhibition of NBC-3 activity by CFTR. These data suggest that the PDZ domain and the formation of a complex are essential for regulation of NBC-3 activity by CFTR.

Cystic fibrosis is associated with chronic inflammation of the airways (30). A question has been raised as to whether the inflammation is secondary to infection by pathogens or caused by some intrinsic defect in the ability of CFTR to regulate the immune response. Although this topic is still controversial, some evidence exists that CFTR can directly interact in airway epithelia with the chemokine RANTES (regulated on activation, normal T cell expressed and secreted), again through an interaction with scaffolding proteins (23). Expression of CFTR appears to enhance the expression of RANTES by modulation of gene expression that is dependent on the formation of a signal transduction complex consisting of the C-terminal PDZ-interacting domain of CFTR and EBP50. Although it is not entirely clear how critical this signaling cascade is in the pathophysiology of CF, it does provide a tantalizing hypothesis that CFTR may regulate mucosal immunity through its ability to bind to a variety of scaffolding molecules.

	WHAT IS THE FUNCTIONAL ROLE OF THE PDZ DOMAIN OF CFTR?

TOP ABSTRACT CARBOXYL TERMINUS OF CFTR CAL AND TRAFFICKING OF... NHE-RF, E3KARP, AND CAP70... DYNAMIC INTERACTION AT THE... PDZ DOMAIN OF CFTR... WHAT IS THE FUNCTIONAL... REFERENCES

 
The importance for CFTR in human biology comes from the role of mutant CFTR in causing the symptoms associated with cystic fibrosis (31). Using the impact of mutant CFTR as a gauge of its importance, one may ask about the severity of disease associated with mutations in the C terminus. Several years ago, our group reported the identification of a 6.8-kb deletion (del14a) and a nonsense mutation (S1455X) in the CFTR genes of a mother and her youngest daughter with isolated elevated sweat chloride concentrations but with no evidence of pulmonary or pancreatic disease characteristic of cystic fibrosis. Further study showed that the S1455X-CFTR mutant generated cAMP-activated whole-cell chloride currents similar to wild-type CFTR. These data are consistent with the relatively normal lung and pancreatic function observed in the mother and her daughter (32). Further study did reveal changes in the nasal potential difference indicative of altered Cl^– transport (G. Cutting, personal communication). Thus, mutations in the C-terminal region of CFTR can be associated with elevated sweat chloride concentrations without seriously affecting the lung and pancreas. The data suggest that the terminal 26 amino acids of CFTR may play a key functional role in the sweat gland, whereas in other tissues the effect may be more subtle. When the S1455X mutant is expressed in polarized, heterologous epithelial cells, a significant portion accumulates at the lateral membrane. The suggestion is that removal of the C-terminal 26 amino acids reduces the stability of CFTR in the apical cell membrane, destabilizing the protein at the apical domain and causing it to accumulate in the basolateral membrane.

Two studies have suggested that the role of PDZ domain proteins in CFTR biology may be subtle. Benharouga and coworkers (33) disrupted the binding of CFTR, using C-terminal deletions, C-terminal epitope tag attachments, or overexpression of a dominant-negative NHE-RF mutant. They observed no effect on CFTR expression, metabolic stability, or function in nonpolarized cells or on the apical localization of CFTR in polarized tracheal, pancreatic, intestinal, and renal epithelia. Interestingly, they did observe that NHE-RF enhances the cAMP-dependent stimulation of CFTR Cl^– channel currents in intact cells.

Ostedgaard and coworkers (34) also studied deletion mutants in the C-terminal tail of CFTR. All of the mutated proteins studied localized predominantly to the apical membrane and generated transepithelial Cl^– currents. They concluded that C-terminal sequences were not absolutely required for apical expression in airway epithelia. They did show, however, that deleting an acidic cluster near the C terminus reduced both the channel-opening rate and transepithelial Cl^– transport. Again, the data point to a role of the C-terminal domain in altering channel gating and perhaps regulation.

There are limited data on a small number of individuals with the S1455X mutation, which makes it difficult to generalize on the role of the C terminus in CFTR biology. However, taken together, the data suggest that the PDZ domain of CFTR does play a role in increasing the efficiency of CFTR by increasing its stability in the apical cell membrane, altering trafficking at the TGN, enhancing activation by protein kinase A, and increasing channel gating.

CONCLUSIONS
CFTR functions as a Cl^– channel and regulates the function of other ion channels (2). The binding of CFTR to multiple PDZ domain proteins suggests that CFTR is part of a three-dimensional network in which PDZ domain protein molecules bind to one or more CFTR molecules, as well as to regulatory molecules and the cytoskeleton, ultimately forming a multimolecular functional complex.

	FOOTNOTES

 
Supported by the Cystic Fibrosis Foundation Research Development Program (W.B.G.) and by National Institutes of Health grants DK-48977 (W.B.G.) and HL-47122 (W.B.G.).

(Received in original form June 19, 2003; accepted in final form August 29, 2003)

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TOP ABSTRACT CARBOXYL TERMINUS OF CFTR CAL AND TRAFFICKING OF... NHE-RF, E3KARP, AND CAP70... DYNAMIC INTERACTION AT THE... PDZ DOMAIN OF CFTR... WHAT IS THE FUNCTIONAL... REFERENCES

 

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