PKHD1
Function
Promotes ciliogenesis in renal epithelial cells and therefore participates in the tubules formation and/ or ensures the maintenance of the architecture of the lumen of the kidney (By similarity). Has an impact on cellular symmetry by ensuring correct bipolar cell division through the regulation of centrosome duplication and mitotic spindle assembly and by maintaining oriented cell division (OCD) during tubular elongation through planar cell polarity (PCP) pathway (PubMed:20554582). During epithelial cell morphogenesis regulates also cell-cell and cell-matrix adhesion and participates in cell motility (By similarity). Promotes cell-cell contact through the positive regulation of PTK2 kinase activity leading to either positive regulation of epithelial cell proliferation through the HRAS/RAF1 pathways, or negative regulation of apoptosis through the PDK1/AKT1 pathway (By similarity). May act in collecting-duct and biliary differentiation (PubMed:11919560). May participate in the regulation of the cholangiocytes proliferation and the CCN2 production in an CXCL8-dependent manner (PubMed:30898581).
Involvement in disease
Polycystic kidney disease 4, with or without polycystic liver disease
PKD4
A severe form of polycystic kidney disease affecting the kidneys and, in some cases, the hepatic biliary tract. The clinical spectrum is widely variable, with most cases presenting during infancy. The fetal phenotypic features classically include enlarged and echogenic kidneys, as well as oligohydramnios secondary to a poor urine output. Up to 50% of the affected neonates die shortly after birth, as a result of severe pulmonary hypoplasia and secondary respiratory insufficiency. In the subset that survives the perinatal period, morbidity and mortality are mainly related to severe systemic hypertension, renal insufficiency, and portal hypertension due to portal-tract fibrosis. PKD4 inheritance is autosomal recessive.
None
The disease is caused by variants affecting the gene represented in this entry.
Loss-of-function PKHD1 variations may cause autosomal dominant polycystic liver disease (PCLD) in patients that lack variations in known causative genes, such as PRKCSH and SEC63.
Post-translational modifications
Several proteolytic cleavages occur within the extracellular domain, whereas at least one cleavage occurs within the cytoplasmic domain (PubMed:16956880). Cleaved by a probable proprotein convertase which produces an extracellular domain (polyductin extracellular domain, (PECD)) and a C-terminal fragment (polyductin transmembrane fragment (PTM)) which are tethered together by disulfide bonds (PubMed:17470460). This extracellular domain (PECD) is then shed from the primary cilium by activation of a member of the ADAM metalloproteinase disintegrins family, resulting in concomitant release of an intra-cellular C-terminal fragment (ICD) via a gamma-secretase-dependent process (PubMed:17470460). The proteolytic cleavage of the C-terminal intracellular fragment (ICD) is controlled by cytosolic calcium concentration and activation of PKC (PubMed:16956880).
Palmitoylated. Palmitoylation facilitates membrane targeting and the trafficking to the cilia.
N-glycosylated.
Tissue Specificity
Predominantly expressed in fetal and adult kidney. In the kidney, it is found in the cortical and medullary collecting ducts. Also present in the adult pancreas, but at much lower levels. Detectable in fetal and adult liver. Rather indistinct signal in fetal brain.
Cellular localization
- Cell membrane
- Single-pass type I membrane protein
- Cytoplasm
- Cell projection
- Cilium
- Cytoplasm
- Cytoskeleton
- Cilium basal body
- Cytoplasm
- Cytoskeleton
- Spindle
- Chromosome
- Centromere
- Apical cell membrane
- Nucleus
- Secreted
- Extracellular exosome
- Secreted
- Endoplasmic reticulum
- Golgi apparatus
- The intracellular C-terminal fragment (ICD) translocates to the nucleus and is not detected in primary cilia (PubMed:16956880, PubMed:17470460). The extracellular domain (PECD) traffics beyond the mid-Golgi and localizes on exosome like vesicles (ELVs) attached to the primary cilium (By similarity). In the urine, the extracellular domain (PECD) exists as a highly abundant secreted form and a less abundant PECD form that is either tethered to or shed with the C-terminal fragment (PTM) in ELVs (By similarity). The majority of full length PKHD1 protein resides at the endoplasmic reticulum and cannot pass beyond the mid-Golgi apparatus and is not detected in primary cilia (By similarity). The intra-cellular C-terminal fragment of 21-kDa translocates to the nucleus. The extracellular domain traffics beyond the mid-Golgi and localizes on exosome like vesicles (ELVs) attached to the primary cilium (By similarity).
Alternative names
FCYT, TIGM1, PKHD1, Fibrocystin, Polycystic kidney and hepatic disease 1 protein, Polyductin, Tigmin