Polycystin: From structure to function

Autosomal dominant polycystic kidney disease ceptor tyrosine kinase inhibitors failed to block cAMP(ADPKD) is a multisystem disease characterized by the mediated proliferation of tubular cells from ADPKD progressive development of numerous fluid-filled cysts patients. These studies indicate that cAMP agonists stimin the kidney, leading to chronic renal failure. Predomiulate PKA-mediated activation of ERK, at a locus distal nant tubular epithelial cell abnormalities associated with to receptor tyrosine kinase in ADPKD cells, but not in ADPKD include abnormal maturation, excessive prolifNHK cells. eration, and fluid secretion. Since polycystin 1 and polyThe basis for this fundamental difference in the prolifcystin 2 have been cloned, more recent studies have erative response of ADPKD and NHK cells to cAMP focused on defining the mechanism through which strucagonists, and how this difference may be related to structural alterations in these genes give rise to the tubular tural alterations in the polycystin molecules raises a numepithelial cell abnormalities characteristic of ADPKD. ber of questions that need to be addressed by further Polycystin 1 has 9 to 11 transmembrane domains, a large study: amino terminal extracellular tail that appears to be in(1) Is the cAMP-PKA pathway abnormally activated volved in cell-cell and cell-matrix interactions, and a in ADPKD? To demonstrate that the proliferative recytoplasmic carboxy terminus that contains a number of sponse of ADPKD cells to cAMP agonists is relevant to motifs that may interact with the cytoskeleton and play our understanding of the pathophysiology of polycystic an important role in intracellular signaling [1]. In vitro kidney disease, it will be necessary to show that the expression studies have shown that the cytoplasmic docAMP-PKA pathway is indeed activated. There is some main of polycystin 1 contains sites that are phosphoryindirect evidence in support of this activation. In the lated by protein kinase A and c-src [2] and may be inmurine pcy/pcy model of PKD, cystogenesis is associated volved in the protein kinase C a dependent and c-Jun with a progressive increase in renal cAMP content [5]. N-terminal kinase dependent activation of transcription Cysts from human ADPKD patients contain micromolar factors, including AP-1 [3]. concentrations of ATP and metabolites of ATP, presumDespite these advances, the mechanisms underlying ably released from cyst lining epithelial cells [6]. In theexcessive tubular epithelial cell proliferation in ADPKD ory, this concentration of ATP is sufficient to activate renal have not been defined. In this issue of Kidney Internaepithelial cell purinergic receptors, increasing secretion of tional, Yamaguchi and colleagues provide evidence that fluid into the cyst lumen. However, further studies are cyclic AMP (cAMP) may play a critical role as a second needed to determine whether intracellular activation of messenger in a signaling pathway leading to tubular epithe cAMP-PKA pathway occurs in ADPKD. thelial cell proliferation and fluid secretion in ADPKD (2) If the cAMP-PKA pathway is indeed activated in [4]. In tubular epithelial cells derived from normal huADPKD, how does this relate to structural abnormalities man kidney (NHK), agonists of the cAMP signaling sysin the polycystin 1 and/or polycystin 2 gene products? tem block basal and growth factor-mediated activation of Cystogenic epithelium in ADPKD is often described as the extracellular signal-regulated protein kinase (ERK) having a “fetal-like” phenotype, characterized by persispathway and inhibit proliferation. In contrast, Yamatent expression of genes expressed during embryogeneguchi et al report that agonists of the cAMP signaling sis, by an increased rate of proliferation, and by abnormal system stimulate proliferation of tubular epithelial cells polarity of ion transporters and growth factor receptors. derived from patients with ADPKD. The stimulatory efIt is certainly possible that structural abnormalities in fect of cAMP on proliferation of ADPKD cells was associthe polycystin molecules give rise to a wide variety of ated with activation of the ERK-pathway. Both protein defects in cell-cell and/or cell-matrix interactions during kinase A (PKA) inhibitors and MEK (mitogen-activated, embryogenesis, and may thereby alter the pattern of ERK-activating kinase) inhibitors blocked the proliferagene expression associated with normal tubular epithetive response of ADPKD cells to cAMP. However, relial cell growth and development. The precise mechanism by which these developmental alterations lead to increased cAMP-PKA signaling needs to be defined. An