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FLASH GENE

Symbol

PKD2

contributors: mct/shn/pgu - updated : 19-01-2021

HGNC name	polycystic kidney disease 2 (autosomal dominant)
HGNC id	9009

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	PKD2 polycystic kidney disease 2
Location	4q22.1      Physical location : 88.928.819 - 88.998.928
Synonym name	R48321
	autosomal dominant polycystic kidney disease type II protein
	polycystic kidney disease 2 protein
	polycystin-2
	polycystwin
	transient receptor potential cation channel, subfamily P, member 2
Synonym symbol(s)	PKD4, CD119, TRPP2, PC2, MGC138466, MGC138468, APKD2, PC-2

DNA

TYPE	functioning gene
STRUCTURE	70.11 kb     15 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	Binding site   transcription factor
text structure	transcription factor binding sites E2F, EGRF, Ets, MZF1, Sp1, and ZBP-89

MAPPING

cloned

Y

linked

N

status

confirmed

Map	cen - D4S2462 - D4S1542 - PKD2 PKD2 - D4S2929 - D4S1563 - qter

RNA

TRANSCRIPTS	type	messenger

text	alternatively spliced

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000297 15 - 5073 NP_000288 110 968 adult and fetal kidney (basolateral plasma membrane of kidney tubular epithelial cells), fetal brain and fetal liver 2009 10770959

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       moderately Homo sapiens Digestive liver       moderately Homo sapiens Nervous brain       moderately Homo sapiens Reproductive male system seminal vesicles     lowly Homo sapiens Respiratory lung       moderately Homo sapiens Urinary kidney       highly Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular       moderately Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

fetal

Text	kidney, term syncytiotrophoblast

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N terminus containing a 15-AA sequence that mediates trafficking to the cilium, and a related N-terminal ciliary-targeting sequence similarly to PKD1, that binds ARF4
	six transmembrane spans, a pore forming region, and cytoplasmic N- and C-terminal tails
	N and C terminal second dimerization domain leading to homotetrameric form (N-terminal dimerization domain is not critical for the function of ER PKD2 channels but is required for the function of surface PKD2 channels)
	a PKHD1-binding domain in the intracellular N terminus
	phosphorylation site within its N-terminal domain having significant role for the maintenance of normal glomerular and tubular morphology
	six transmembrane segments (6TM)
	a large extracellular loop between TM1 and 2
	five N-glycosylation sites
	several phosphorylation sites
	a transient receptor potential channel subunit motif (TRP), dimerizing with TRPC1 or PKD1
	a coiled-coil domain including an EF hand calcium binding domain in the C terminus critical for the formation of the complex PKD2/PKD1 , that functions as a homodimerization domain essential for PKD1 binding but not for its self-oligomerization
	C terminus required for the interaction with the
	AKAP5 complex
	Cterm protein contains a Ca(2+)-binding site responsible for channel gating and function

mono polymer

homomer , heteromer , dimer , tetramer

HOMOLOGY

interspecies	ortholog to Pkd2, Mus musculus
	ortholog to Pkd2, Rattus norvegicus

intraspecies

homolog to TRPC1,PKD1

Homologene

FAMILY	voltage gated Ca+ channels family
	polycystin protein family
	transient receptor potential superfamily of cation channels

CATEGORY

signaling , transport channel

SUBCELLULAR LOCALIZATION	plasma membrane,junction
	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,endoplasmic reticulum
	intracellular,cytoplasm,organelle,Golgi
	intracellular,cytoplasm,cytoskeleton,microtubule
text	basolateral plasma membrane of kidney tubular epithelial cells
	localized on the ER membrane as a Ca release channel
	Type II membrane protein
	ER localization plays an important role in the development of normal Left-Right asymmetry
	localized at the endoplasmic reticulum (ER) membrane significantly enhanced Ca2+ release from the ER upon muscarinic acetylcholine receptor (mAChR) stimulation
	besides its localization in the primary cilium, is present in the endoplasmic reticulum (ER), the PM, the adherens junctions and the basolateral cell surface of kidney epithelial cells
	with PKD1, colocalize to cilia, where they may enable a mechano/chemosensory response triggering a rise in intracellular Ca2+
	located in the primary cilium where it is thought to transmit mechanical stimuli into the cell interior

basic FUNCTION	Ca2+ permeable non selective cation channel with a high permeability to Ca2+
	modulating Ca2+ entry in response to G-protein coupled receptor activation and/or store depletion
	mediating mechanosensation in the primary cilium of kidney cells
	function as a nonselective cation channel in the plasma membrane
	acting as a negative regulator of cell growth, and may also play an important role in the regulation of tubulogenesis
	playing a necessary role for the proper growth and differentiation of kidney epithelial cells
	traffics to cilia independently of polycystin-1 by using an N-terminal RVXP motif
	showing a pattern of single-channel conductance, amiloride sensitivity and ion permeability distinct from that of PKD2 alone
	TRP-type Ca(2+)-permeable non-selective cation channel, present and functional in microtubule-containing primary cilia of renal epithelial cells, and having a regulatory role in the sensory function of primary cilia
	in the ER plays a role in cellular Ca2+ homeostasis
	represses cell proliferation through promoting the phosphorylation of eukaryotic translation initiation factor eIF2A by pancreatic ER-resident eIF2 alpha kinase (EIF2AK3)
	important regulator of the translation machinery
	important for regulation of RyR2 function
	calcium permeable nonselective cation channel implicated in the regulation of cardiac development, renal tubular differentiation, and left-to-right (L-R) axis determination
	may be assuming distinct subcellular localizations to exert tissue-specific functions
	protects cells from apoptosis by lowering the Ca2+ concentration in the endoplasmic reticulum (ER)
	having an important function in the modulation of intracellular Ca2+ signalling
	modulating the cleavage of PKD1
	functions as a Ca2+-permeable nonselective cation channel, ER-localized, interacting with the ER Ca2+ channel, inositol 1,4,5-trisphosphate receptor (ITPR1), to promote ER Ca2+ release
	inhibits stretch-activated ions channels
	acting as a Ca2+ release channel of intracellular stores and functionally interact with inositol 1,4,5-trisphosphate receptor-induced Ca2+ release
	also acts as an intracellular Ca2+-release channel in the endoplasmic reticulum (ER) where it interacts with the inositol-1,4,5 trisphosphate (InsP3) receptor and ryanodine receptor
	RP2 and PKD2 function in a common developmental process (
	its expression is required for the movement of PKD1 to the plasma and ciliary membranes
	functions as a non-selective cation channel in the endoplasmic reticulum and possibly at the plasma membrane
	mediates sensory perception on cilia and flagella
	PKD1L1 and PKD2 form a complex that functions as the nodal flow sensor in the motile cilia of the medaka Kupffer's vesicle
	PKD2 modulates intracellular calcium cycling, contributing to the development of heart failure
	PKD2 contributes to Ca2+ transport and cell signaling in renal epithelia and other tissues
	PKD1, PKD2 form an ion channel complex that may mediate ciliary sensory processes and regulate endoplasmic reticulum (ER) Ca2+ release
	role for PKD1, PKD2 in sensing and responding to cellular O2 levels

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

text	cation channel

PATHWAY

metabolism

signaling

for normal tubulogenesis

a component	homodimerizing or heterodimerizing with PKD1 or TRPC1 through their cytoplasmic C terminal tail, 3 PKD2 and 1 PKD1 (disruption of the complex PKD1/PKD2 is involved in the pathogenesis of cyst formation through a mechanosensor action in renal primary cilia for fluid flow)
	heterodimerizing with CBY1, CD2AP, DIAPH1
	forming with TRPC1 a channel with a unique constellation of new and TRPP2/TRPC1-specific properties, activated in response to G-protein-coupled receptor activation
	RP2 forms a calcium-sensitive complex with polycystin 2 (
	member of the TRP family of cation channels and an important PKD1 binding partner
	homodimerization is regulated by three distinct domains and these events regulate formation of the tetrameric PC2 channel
	PKD2 and PDE4C are unique components of an AKAP complex in primary cilia
	its Ca2+ channel activity is important for regulating cAMP signaling
	filamins are important regulators of PKD2 channel function, and further links actin cytoskeletal dynamics to the regulation of this channel protein

INTERACTION

DNA

RNA

small molecule

other,

forms a Ca(2+)-permeable channel in the cell membrane and its function is regulated by cytosolic Ca(2+) levels

protein	polycystic kidney disease 1, PKD1
	transient receptor potential cation channel, subfamily C, member 1, TRPC1
	coassembling with PKD1, by their C terminus coiled coil domains to produce a new channel regulate renal tubular morphology and function and to activate JAK2
	HCLS1 associated protein X-1, HAX1
	GSK3 (N-terminal domain (Ser(76)) is phosphorylated by glycogen synthase kinase 3)
	functionally interacts with ciliary chemosensors
	HAVCR1 (interaction dependent on the ciliary sorting signal of PKD2 and the functionally relevant tyrosine 350 in HAVCR1 supporting recent evidence that PKD2 functionally interacts with chemosensors)
	HERPUD1 (promotes degradation of PKD2 through the ERAD pathway)
	STX5 (STX5 functions to inactivate PKD2 and prevent leaking of Ca2+ from ER stores)
	may form functional homo- or heterotetramers with other subunits, similar to other TRP channels
	CD2-associated protein, CD2AP
	tropomyosin-1, TPM1
	mammalian Diaphanous or Diaphanous-related formin 1 protein, mDia1/Drf1
	Pericentrin, PCNT
	PACS-1 and PACS-2
	Alpha-actinin
	ACTN2 associates with polycystin-2 and regulates its channel activity
	TRPC1 (form homotetramers, with distinct functional and regulatory properties, among which there are the presence of four subconductance states in PKD2)
	PKD2 interacts with LCK and regulates NFAT activity in T cells
	PKD1 and ITPR1 in a complementary way to maintain Ca2+ homeostasis
	C terminus of PKD2 strongly interacts with PDZ domains 8-10 and to a weaker extent with PDZ domains 1-3 of INADL
	PKD1Ll1 and PKD2 localise to the cilium and biochemical experiments demonstrate that they can physically interact
	NEK1 phosphorylates WWTR1 at a site essential for the ubiquitination and proteasomal degradation of PKD2
	interacts with ADCY5 through its C terminus
	AURKA binds, phosphorylates, and reduces the activity of PKD2, and, thus, limits the amplitude of Ca(2+) release from the endoplasmic reticulum
	CAMK2A is a PKD2 target that promotes pronephric kidney development and stabilizes cilia
	stimulates the inositol trisphosphate (IP(3)) receptor (IP(3)R), a Ca(2+)-release channel in the endoplasmic reticulum (ER)
	PKD1, PKD2 are both required to amplify inositol-trisphosphate-induced Ca2+ release
	reciprocal functional link between PKD1 and PKD2 which is critically dependent on their interaction
	BBS4 and BBS5 interact directly and coordinate the ciliary removal of polycystin 2
	PKD1L1 acts as an upstream genetic repressor of PKD2
	PKD2-dependent channel of renal primary cilia also requires TRPM3
	in addition to its channel function, PKD2 interacts with and acts as a regulator of a number of other channels, ultimately further affecting intracellular signaling and leading to dysfunction in its absence

cell & other

REGULATION

Other	ciliary trafficking of PKD2 is regulated by the BBSome
	Ca2+ sensing mechanism for PKD2 expression and functional regulation in renal epithelial cells

ASSOCIATED DISORDERS

corresponding disease(s)

PKD2

related resource

Polycystickidneyresearchfoundation

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral somatic mutation       in PKD2 cysts

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed tumor kidney   modulation of the PKD2/STX5 interaction may be a useful target for impacting dysregulated intracellular Ca2+ signaling associated with polycystic kidney disease

ANIMAL & CELL MODELS

	Pkd2-/- mice die in utero between embryonic day (E) 13.5 and parturition with structural defects in cardiac septation and cyst formation in maturing nephrons and pancreatic ducts. Pkd2WS25/- mice have pancreatic ductal and kidney cysts associated with renal failure and early death
	Pkd2 (+/-) and Pkd1(+/-) : Pkd2 (+/-) mice have mild renal cystic lesions with no adverse effect on survival at 1 year
	Pkd2 (+/-) mice develop hypertension, intracranial vascular abnormalities and vascular smooth muscle cells and have significantly altered intracellular Ca(2+) homeostasis