Parathyroid hormone-related protein
Encyclopedia
Parathyroid hormone-related protein (or PTHrP) is a protein
member of the parathyroid hormone family
. It is occasionally secreted by cancer
cells (breast cancer
, certain types of lung cancer
including squamous cell carcinoma
). However, it also has normal functions.
, autocrine
, paracrine
, and intracrine
hormone. It regulates endochondral bone development by maintaining the endochondral growth plate at a constant width. It also regulates epithelial-mesenchymal interaction
s during the formation of the mammary glands.
secretes PTHrP, this can lead to hypercalcemia. As this is sometimes the first sign of the malignancy, hypercalcemia caused by PTHrP is considered a paraneoplastic phenomenon. PTHR1 is responsible for most cases of humoral hypercalcemia of malignancy.
PTHrP shares the same N-terminal end as parathyroid hormone and therefore it can bind to the same receptor, the Type I PTH receptor (PTHR1
). PTHrP can simulate most of the actions of PTH including increases in bone resorption and distal tubular calcium reabsorption, and inhibition of proximal tubular phosphate transport.
However, PTHrP is less likely than PTH to stimulate 1,25-dihydroxyvitamin D production. Therefore, PTHrP does not increase intestinal calcium absorption.
transcript variants encoding two distinct isoforms have been observed. There is also evidence for alternative translation initiation from non-AUG (CUG and GUG) start sites, in-frame and downstream of the initiator AUG codon, to give rise to nuclear forms of this hormone.
with KPNB1
and Arrestin beta 1
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
member of the parathyroid hormone family
Parathyroid hormone family
Parathyroid hormone is a polypeptidic hormone that elevates calcium level by dissolving the salts in bone and preventing their renal excretion. The 'parathyroid hormone-related protein' is structurally related to PTH and seems to play a physiological role in lactation, possibly as a hormone for...
. It is occasionally secreted by cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
cells (breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, certain types of lung cancer
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
including squamous cell carcinoma
Squamous cell carcinoma
Squamous cell carcinoma , occasionally rendered as "squamous-cell carcinoma", is a histologically distinct form of cancer. It arises from the uncontrolled multiplication of malignant cells deriving from epithelium, or showing particular cytological or tissue architectural characteristics of...
). However, it also has normal functions.
Function
PTHrP acts as an endocrineEndocrine system
In physiology, the endocrine system is a system of glands, each of which secretes a type of hormone directly into the bloodstream to regulate the body. The endocrine system is in contrast to the exocrine system, which secretes its chemicals using ducts. It derives from the Greek words "endo"...
, autocrine
Autocrine signalling
Autocrine signaling is a form of signalling in which a cell secretes a hormone or chemical messenger that binds to autocrine receptors on the same cell, leading to changes in the cell...
, paracrine
Paracrine signalling
Paracrine signalling is a form of cell signalling in which the target cell is near the signal-releasing cell.-Local action:Some signalling molecules degrade very quickly, limiting the scope of their effectiveness to the immediate surroundings...
, and intracrine
Intracrine
Intracrine refers to a hormone that acts inside a cell. Steroid hormones act through intracellular receptors and, thus, may be considered to be intracrines. In contrast, peptide or protein hormones, in general, act as endocrines, autocrines, or paracrines by binding to their receptors present on...
hormone. It regulates endochondral bone development by maintaining the endochondral growth plate at a constant width. It also regulates epithelial-mesenchymal interaction
Epithelial-mesenchymal transition
Epithelial-mesenchymal transition or transformation is a hypothesized program of development of biological cells characterized by loss of cell adhesion, repression of E-cadherin expression, and increased cell mobility...
s during the formation of the mammary glands.
Tooth eruption
PTHrP is critical in the intraosseous phase of tooth eruption where it acts as a signalling molecule to stimulate local bone resorption. Without PTHrP, the bony crypt surrounding the tooth follicle will not resorb, and therefore the tooth will not erupt. In the context of tooth eruption, PTHrP is secreted by the cells of the Reduced Enamel Epithelium.Mammary glands
It aids in normal mammary gland development. It is necessary for maintenance of the mammary bud. Loss of PTHrP or its receptor causes the mammary bud cell fate to change back into epidermis. In lactation, it may regulate in conjunction with the calcium sensing receptor the mobilization and transfer of calcium to the milk, as well as placental transfer of calcium.Humoral hypercalcemia of malignancy
PTHrP is related in function to the "normal" parathyroid hormone. When a tumorTumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
secretes PTHrP, this can lead to hypercalcemia. As this is sometimes the first sign of the malignancy, hypercalcemia caused by PTHrP is considered a paraneoplastic phenomenon. PTHR1 is responsible for most cases of humoral hypercalcemia of malignancy.
PTHrP shares the same N-terminal end as parathyroid hormone and therefore it can bind to the same receptor, the Type I PTH receptor (PTHR1
Parathyroid hormone receptor 1
Parathyroid hormone/parathyroid hormone-related peptide receptor also known as parathyroid hormone 1 receptor is a protein that in humans is encoded by the PTH1R gene...
). PTHrP can simulate most of the actions of PTH including increases in bone resorption and distal tubular calcium reabsorption, and inhibition of proximal tubular phosphate transport.
However, PTHrP is less likely than PTH to stimulate 1,25-dihydroxyvitamin D production. Therefore, PTHrP does not increase intestinal calcium absorption.
Genetics
Four alternatively splicedAlternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
transcript variants encoding two distinct isoforms have been observed. There is also evidence for alternative translation initiation from non-AUG (CUG and GUG) start sites, in-frame and downstream of the initiator AUG codon, to give rise to nuclear forms of this hormone.
Discovery
The protein was first isolated in 1987 by T.J. Martin's team at the University of Melbourne. Miao et al. showed that disruption of the PTHrP gene in mice caused a lethal phenotype and distinct bone abnormalities, suggesting that PTHrP has a physiological function.Interactions
Parathyroid hormone-related protein has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with KPNB1
KPNB1
Importin subunit beta-1 is a protein that in humans is encoded by the KPNB1 gene.-Interactions:KPNB1 has been shown to interact with NUP98, Karyopherin alpha 1, KPNA3, Karyopherin alpha 2, SMN1, Parathyroid hormone-related protein, Nucleoporin 62, RANBP2, Ran , RANBP1, NUP50, P53, NUP153 and...
and Arrestin beta 1
Arrestin beta 1
Arrestin, beta 1, also known as ARRB1, is a protein which in humans is encoded by the ARRB1 gene.- Function :Members of arrestin/beta-arrestin protein family are thought to participate in agonist-mediated desensitization of G protein-coupled receptors and cause specific dampening of cellular...
.