Polycystin-1 (PC-1), the product of PKD1, is a very large protein (4300 amino acids), and is a membrane glycoprotein widely expressed in epithelial cells.
It is also expressed in
Polycystin-2 (PC-2), the product of PKD2, is a smaller protein (968 amino acids) mainly present in the endoplasmic reticulum membrane, but also in the cell plasma membrane.
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Wikigenes includes links to
- NCBI Gene
- NCBI SNP
- iHOP resource
CHEMICAL STRUCTURE AND IMAGES
When relevant for the function
- Primary structure
- Secondary structure
- Tertiary structure
- Quaternary structure
Protein Aminoacids Percentage
The Protein Aminoacids Percentage gives useful information on the local environment and the metabolic status of the cell (starvation, lack of essential AA, hypoxia)
Protein Aminoacids Percentage (Width 700 px)
SYNTHESIS AND TURNOVER
PC-1 and -2 are joined via a domain in the carboxy-tail of PC-1, and appear to act in concert.
PC-2 acts as a Ca2+ channel. Although the exact function of these two proteins has not been fully elucidated, there appear to be at least four membrane effects:
- activation of PC-1 causes activation of PC-2 and release of Ca2+ from the endoplasmic reticulum into the cytoplasm.
- PC-1 can also cause entry of extracellular Ca2+ via cell membrane PC-2.
- PC-1 activates heterotrimeric G-proteins, thus affecting activity of adenylyl cyclase, MAP kinases and other effectors that can effect fluid secretion, proliferation and differentiation.
- PC-1 can induce cell cycle arrest via activation of the JAK-STAT signalling pathway.
In summary, activation of PC-1 and -2 appears to cause an increase in intracellular Ca2+ levels, causing a reduction in cAMP via direct inhibition of cAMP and stimulation of phosphodiesterase activity, which metabolizes cAMP. They also have an anti-mitotic effect, causing cell cycle arrest.<br
Emerging evidence of a link between the polycystins and the mTOR pathways 2009
PC-1 tail reacts with tuberin, the product of the TSC2 gene. Mutations of this gene lead to tuberous sclerosis, a much less common disorder than ADPKD, but which is also associated with renal cysts. PC-1 may normally suppress mTOR activity via tuberin, and mutations of PC-1 may lead to aberrant mTOR activation, resulting in abnormal growth, proliferation and de-differentiation of tubular epithelial cells, resulting in cysts. mTOR, as its name indicates, is inhibited by the immunosuppressant drug rapamycin.
All renal epithelial cells (except for collecting duct intercalated cells) possess a single primary cilium. Primary cilia contain a number of unique proteins which are critical for the normal function of these organelles, including PC-1 and -2. It seems that primary cilia act as mechanosensors, since flow-induced bending leads to a rise in intracellular calcium levels. This appears to be modulated via the ciliary polycystin complex, with PC-2 mediating the flow-induced influx of extracellular calcium. The loss of function of PKD1 or PKD2 in ADPKD results in excessive and uncontrolled tubular growth and fluid secretion: in other words, a loss of normal regulatory processes controlling tubule growth. Since ADPKD kidneys initially develop normally, PKD1 and PKD2 do not seem to be necessary for renal tubule formation, but may be required to regulate subsequent tubular growth. Thus these two genes may be part of a program regulating renal tubular size, by means of the mechanosensitive Ca2+ signalling pathway in renal epithelial primary cilia that inhibits renal tubular growth. This could also explain why similar disorders of growth are also seen in ADPKD in other organs, such as hepatic and pancreatic cysts and vascular aneurysms. A perplexing question regarding ADPKD is the nature of the mutational mechanism. Since the disease is autosomal dominant, all cells contain one normal gene and one mutated gene. Thus all cells should be able to produce normal PC-1 and -2. To explain this anomaly, the ‘two-hit’ hypothesis has been proposed. This suggests that in addition to the germ line mutation of one allele, a somatic mutation occurs in some cells of the second, normal allele, which thus becomes inactivated and unable to produce PC-1 or -2.
- Cell signaling and Ligand transport
- Structural proteins
Cysts are originally connected to the mother collecting duct, but eventually the connection closes off, and the cysts can then only enlarge by a process of increased proliferation of mural epithelial cells and secretion.
The cells undergo a remarkable phenotypic change, from the usual non-proliferative and reabsorptive phenotype of collecting duct principal cells, to a secretory and proliferative phenotype; the prototype cell involved is considered to be the cortical collecting duct (CCD) principal cell. These cells normally reabsorb NaCl: the sodium enters the luminal membrane via the epithelial sodium channels (ENaC); the chloride ions via chloride channels. The driving force is the low intracellular sodium concentration caused by the basolateral Na+ K+ ATPase. Potassium ions exit the luminal membrane via Renal Outer Medullary K+ (ROMK) channels driven mainly by the negative lumen potential caused by the inwardly directed sodium current. Water also enters these cells across the luminal membrane via vasopressin-sensitive Aquaporin 2 channels. Cell growth is dependent on the activity of basolateral Na+ K+ ATPase and Na+ Cl- K+ (NKCC2) co-transporter, not constitutively active in CCD cells. Na+ and Cl- are the main solutes secreted with the fluid, dependent upon a secondary active transport of chloride from the blood into the urine. Chloride ions enter the epithelial cells via the NKCC2 co-transporter in the basolateral membrane, and are then extruded from the luminal membrane into the cyst lumen via chloride channels. The luminal chloride channels appear to be of two types: (i) cystic fibrosis conductor regulator (CFTR) channels, stimulatedby cAMP pathway, and (ii) purinergic chloride channels, driven by ATP secreted into the cyst lumen. This powerful chloride secretion creates a negative luminal potential, enabling a passive paracellular flux of sodium ions into the lumen. The epithelial sodium channel ENaC, usually responsible for sodium reabsorption across the collecting duct principle cell luminal membrane, appears to be suppressed by expression of CFTR, thus facilitating net chloride secretion into the cyst lumen. The secretion of sodium chloride then causes an osmotically-driven water flux. Thus, sodium chloride and then water are secreted into the lumen of the cyst.
The altered cell polarization may be mediated by the missing interaction between polycystin-1 and E-cadherin
EGF and IGF-1 activate proliferation via receptor tyrosine kinase, Raf-1, MEK-1 and ERK.
cAMP activates B-Raf, a kinase normally quiescent in the tubular epithelium, and this increases the activation of ERK, leading to increased cell division. In a recent study, intracellular Ca2+ levels were measured in normal human kidney (NHK) cells and in epithelial cystic cells from ADPKD. Steady state levels were 20nM lower in ADPKD cells than in NHK cells; instead elevation in intracellular Ca2+ blocked cAMP-dependent B-Raf and ERK activation. Thus the mitogenic effect of cAMP in ADPKD appears to be mediated via a lower intracellular Ca2+, due to lack of normal PKD1 or PKD2 gene products.
Cyclic AMP in PKD thus causes enlargement of cysts via two mechanisms:(i) stimulating secretion of fluid into the cyst lumen; and (ii) stimulating growth of the epithelial cells lining the cyst.
Polycystin cAMP cell proliferation
Calcium Restriction Allows cAMP Activation of the B-Raf/ERK Pathway, Switching Cells to a cAMP-dependent Growth-stimulated Phenotype*2004
Papers Polycystin cytokines