Type IIa Na͞Pi cotransporters are expressed in renal proximal brush border and are the major determinants of inorganic phosphate (Pi) reabsorption. Their carboxyl-terminal tail contains information for apical expression, and interacts by means of its three terminal amino acids with several PSD95͞DglA͞ZO-1-like domain (PDZ)-containing proteins. Two of these proteins, NaPi-Cap1 and Na͞H exchanger-regulatory factor 1 (NHERF1), colocalize with the cotransporter in the proximal brush border. We used opossum kidney cells to test the hypothesis of a potential role of PDZ-interactions on the apical expression of the cotransporter. We found that opossum kidney cells contain NaPi-Cap1 and NHERF1 mRNAs. For NHERF1, an apical location of the protein could be documented; this location probably reflects interaction with the cytoskeleton by means of the MERM-binding domain. Overexpression of PDZ domains involved in interaction with the cotransporter (PDZ-1͞ NHERF1 and PDZ-3͞NaPi-Cap1) had a dominant-negative effect, disturbing the apical expression of the cotransporter without affecting the actin cytoskeleton or the basolateral expression of Na͞K-ATPase. These data suggest an involvement of PDZ-interactions on the apical expression of type IIa cotransporters.opossum kidney cells ͉ Na͞H exchanger-regulatory factor 1 ͉ proximal tubules P roximal tubular reabsorption of inorganic phosphate (P i ) plays a key role in P i metabolism (1, 2). Up to 80% of the renal reabsorption of P i is mediated by the brush border membrane (BBM)-associated type IIa Na͞P i -cotransporters (NaPi IIa; refs. 3 and 4; for review, see ref.2). According to their key physiological role, these cotransporters are up-regulated by factors that stimulate renal reabsorption of P i (ref. 5; for review see ref.2), whereas they are down-regulated by phosphaturic factors (refs. 6 and 7; for review, see ref. 2). Their expression is also affected in pathological states associated with P i wasting, such as X-linked hypophosphatemic rickets: a primary defect on the PHEX gene leads by a yet-unknown mechanism to a reduced expression of NaPi IIa (8, 9). Many of the proximal tubular characteristics in terms of P i handling are retained in a cell line derived from opossum kidney (OK) cells. These OK cells contain an endogenous NaPi IIa cotransporter (NaPi4) apically located and regulated by the same hormones and factors as NaPi IIa cotransporters in proximal tubules (6,10,11).NaPi IIa cotransporters are predicted to contain eight transmembrane domains with intracellular N-and C-terminal tails (12). The C-terminal tail contains two signals involved in apical expression: a terminal PSD95͞DglA͞ZO-1-like domain (PDZ)-binding motif (TRL) and an internal determinant (13). The C-terminal tail interacts, by means of TRL residues, with several PDZ-containing proteins, among them NaPi-Cap1 and Na͞H exchanger-regulatory factor 1 (NHERF1; ref. 14). Similar to NaPi IIa, both proteins are located on the BBM of proximal tubules (14, 15). NaPi-Cap1 is a protein of about 500 residues that co...

The study of calcium channels in molecular mechanisms of cancer transformation is still a novel area of research. Several studies, mostly conducted on cancer cell lines, however support the idea that a diversity of plasma membrane channels participates in the remodeling of Ca2+ homeostasis, which regulates various cancer hallmarks such as uncontrolled multiplication and increase in migration and invasion abilities. However few is still understood concerning the intracellular signaling cascades mobilized by calcium influx participating to cancer cell behavior. This review intends to gather some of these pathways dependent on plasma membrane calcium channels and described in prostate, breast and lung cancer cell lines. In these cancer cell types, the calcium channels involved in calcium signaling pathways promoting cancer behaviors are mostly non-voltage activated calcium channels and belong to the TRP superfamily (TRPC, TPRPV and TRPM families) and the Orai family. TRP and Orai channels are part of many signaling cascades involving the activation of transmembrane receptors by extracellular ligand from the tumor environment. TRPV can sense changes in the physical and chemical environment of cancer cells and TRPM7 are stretch activated and sensitive to cholesterol. Changes in activation and or expression of plasma-membrane calcium channels affect calcium-dependent signaling processes relevant to tumorigenesis. The studies cited in this review suggest that an increase in plasma membrane calcium channel expression and/or activity sustain an elevated calcium entry (constitutive or under the control of extracellular signals) promoting higher cell proliferation and migration in most cases. A variety of non-voltage-operated calcium channels display change expression and/or activity in a same cancer type and cooperate to the same process relevant to cancer cell behavior, or can be involved in a different sequence of events during the tumorigenesis. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.