VIP (vasoactive intestinal peptide)
2013-08-01 Terry Moody AffiliationNational Cancer Institute, Center for Cancer Research, Office of the Director, 31 Center Drive, Bldg 31, Rm 4A48, Bethesda, Maryland 20892, USA
Identity
HGNC
LOCATION
6q25.2
IMAGE
LEGEND
Structure of human preproVIP. VIP is derived from the 170 amino acid precursor protein preproVIP. Initially the signal peptide (1-20) is cleaved by signal proteases to generate proVIP. ProVIP (22-170) is metabolized to (22-79), PHM (81-107), (111-122), VIP (125-152) and (156-170) by prohormone convertases. Carboxypeptidase B-like enzymes cleave basic R and K. The C-terminal of PHM and VIP is amidated when G is metabolized by peptidylglycine alpha-amidating monooxygenase (PAM) enzymes.
LOCUSID
ALIAS
PHM27
DNA/RNA
Note
The human VIP gene encodes 7 exons and is localized to chromosome 6q25.2 (Fahrenkrug, 2010).
Description
The VIP gene spans 8837 bp.
Transcription
The gene transcript has 1601 bp.
Proteins
Description
Said and Mutt (1970) sequenced an acid extractable peptide from the porcine duodenum which decreased systemic arterial pressure and increased heart rate, stroke volume, mesenteric and femoral blood flow in the dog. The 27 amino acid peptide was named vasoactive intestinal peptide (VIP). VIP is metabolized (Bodner et al., 1985) from a 170 amino acid precursor protein (preproVIP). Each exon encodes a distinct domain of the preproVIP 5 untranslated regions of the mRNA (exon I); signal peptide of preproVIP (exon II); N-terminal peptide (exon III); peptide histidine methionine (PHM) (exon IV); VIP (exon V); C-terminal of preproVIP (exon VI); untranslated region of the mRNA (exon VII). VIP and PHM, which have 48% amino acid homology, are in adjacent exons and the introns surrounding these exons are highly conserved. The substrate prepro-VIP is initially metabolized by a signal protease to form the product 149 amino acid pro-VIP. Pro-VIP is metabolized by prohormone convertases to VIP-GKR (preproVIP(125-155)) and PHM-GKR (preproVIP(81-110)). The basic amino acids are cleaved by carboxypeptidase B and the G is metabolized to an amide by PAM enzymes. Thus the N-terminal of VIP and PHM is free whereas the C-terminal is amidated. VIP is structurally related to pituitary adenylate cyclase activating polypeptide (PACAP) (Arimura, 1992). VIP has a β-turn at residues 2-5 and 7-10 followed by an α-helix at residues 11-26 (Vaudry et al., 2009).
VIP binds with high affinity to 2 GPCR (VPAC1 and VPAC2) which are members of the class II or class B secretin-like receptors but not PAC1 which binds PACAP with high affinity (Harmar et al., 2012). The activated VPAC1 or VPAC2 interacts with a stimulatory guanine nucleotide binding protein (Gs) causing increased adenylylcyclase activity resulting in elevated cAMP. The increased cAMP activates protein kinase (PK) A causing phosphorylation of various proteins such as CREB leading to altered gene expression.
VIP binds with high affinity to 2 GPCR (VPAC1 and VPAC2) which are members of the class II or class B secretin-like receptors but not PAC1 which binds PACAP with high affinity (Harmar et al., 2012). The activated VPAC1 or VPAC2 interacts with a stimulatory guanine nucleotide binding protein (Gs) causing increased adenylylcyclase activity resulting in elevated cAMP. The increased cAMP activates protein kinase (PK) A causing phosphorylation of various proteins such as CREB leading to altered gene expression.
Expression
VIP is produced in neurons within the adrenals, brain, gastrointestinal (GI) tract, heart, pituitary and pancreas (Sundler et al., 1988). VIP addition to the adrenals causes catecholamine release (Card et al., 1988). VIP expression in the suprachiasmatic nucleus of the brain is altered by light-dark cycles (Gozes et al., 1989) suggesting that it may play a role in circadian cycles. VIP reduction in knockout mice is associated with human motility disorders (Moody et al., 2011). In the heart, VIP-containing nerve fibers are abundant in arteries but not veins and venules (Sundler et al., 1988). VIP secretion from pancreatic neurons alters enzyme and electrolyte secretion (Konturek et al., 1976). In the pituitary, VIP gene expression is regulated by estrogen leading to altered prolactin secretion (Montagne et al., 1995). VIP is present in and secreted from immune cells especially Th2 cells altering cytokine and chemokine production (Gonzalez-Rey et al., 2007). The VIP gene is in NSCLC cells and its expression is regulated in a PKC and cAMP dependent manner (Davidson et al., 1996). VIP is present in neuroblastoma and pheochromocytoma (Beinfeld et al., 1988). The results indicate that VIP is present in normal neurons and cancer cells.
Localisation
PreproVIP is stored in dense core neurosecretory granules in cells. PHM, proVIP and VIP are secreted when cAMP is elevated. While VIP has potent biological activity, PHM and proVIP are also active (Fahrenkrug, 1991). In NSCLC cells, the ratio of PHM/ proVIP/VIP is 1/3/1 respectively (Moody et al., 2003). VIP is metabolized by neutral endopeptidase and has a half life of 2 min (Henning and Sawmiller, 2001).
Function
VIP is a cotransmitter with nitric oxide and carbon monoxide of nonadrenergic, noncholinergic vascular and nonvascular smooth muscle (Said and Rattan, 2004). It is a cotransmitter with acetylcholine in exocrine glands (Fahrenkrug, 1993). VIP promotes neuronal survival (Brenneman and Eiden, 1986). VIP causes prolactin secretion from the pituitary (Reichlin, 1988) and catecholamine release from the adrenal medulla (Malhotra et al., 1988). In the immune system VIP regulates T cell traffic and proliferation (Ottaway, 1987).
Homology
VIP has 67% sequence homology with PACAP-27. The sequence for VIP is identical in the human, bovine, porcine and rat.
Mutations
Note
The VIP gene is altered in patients with idiopathic pulmonary arterial hypertension (IPAH) (Haberl et al., 2007). The 3 untranslated region in exon 7 is mutated (g.8129T>C) leading to reduced VIP serum levels and higher pulmonary artery pressure (Zhang et al., 2009).
Implicated in
Entity name
Pancreatic cancer
Note
VIPomas were described by Verner and Morrison (1958). Most of the VIPomas occur in the pancreas leading to diarrheal fluid similar to that seen in patient with cholera, hence the term pancreatic cholera of watery diarrhea, hypokalemic and achlorhydric (WDHA) has been used. The plasma VIP levels are significantly elevated in patients with VIPomas (Long et al., 1981).
Entity name
Lung cancer
Note
The VIP gene is expressed in numerous lung cancer cell lines (Davidson et al., 1996). Pro-VIP and VIP are present in lung cancer cell lines (Moody et al., 2003). VIP (10 nM) increases lung cancer colony formation which is inhibited by the VPAC1 antagonist VIPhybrid (Moody et al., 1993). High densities of VPAC1 are present in lung cancer cells (Moody and Gozes, 2007).
Entity name
Breast cancer
Note
VIP addition to breast cancer cells causes transactivation of the EGF receptor and HER2 (Valdehita et al., 2009). Addition of VIP-camptothecin conjugates causes apoptosis of breast cancer cells (Moody et al., 2007).
Entity name
Renal cell carcinoma
Note
Addition of 100 nM VIP to renal cancer cells decreases proliferation (Vacas et al., 2012). High concentrations of VIP may cause differentiation of cancer cells (Hoosein et al., 1989).
Entity name
Prostate cancer
Note
High densities of VPAC1 were detected in prostate cancer cell lines (Reubi et al., 2000).
Entity name
Colon cancer
Note
123I-VIP can be used to visualize colon cancer tumors in patients (Raderer et al., 1998).
Entity name
Diabetes
Note
Overexpression of the VIP gene in mouse pancreatic beta cells resulted in reduced blood glucose and insensitivity to glucose intolerance (Passemard et al., 2011).
Entity name
Bronchial asthma
Note
VIP nerves are absent in severely asthmatic subjects. Mice with targeted deletion of the VIP gene exhibit histopathologic features of airway inflammation (Said et al., 2010).
Entity name
Cardiomyopathy
Note
Hearts were dilated in VIP knockout mice with thinning of the left ventricular wall and increases in right ventricular and left ventricular chamber size resulting from overexpression of cardiomyophathy genes (Szema et al., 2013). VIP is a potent vasodilator and increases the heart rate (Henning and Sawmiller, 2001).
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 1313597 | 1992 | Pituitary adenylate cyclase activating polypeptide (PACAP): discovery and current status of research. | Arimura A et al |
| 2839090 | 1988 | The regulation of vasoactive intestinal peptide synthesis in neuroblastoma and chromaffin cells. | Beinfeld MC et al |
| 2987932 | 1985 | Coding sequences for vasoactive intestinal peptide and PHM-27 peptide are located on two adjacent exons in the human genome. | Bodner M et al |
| 3456568 | 1986 | Vasoactive intestinal peptide and electrical activity influence neuronal survival. | Brenneman DE et al |
| 2898292 | 1988 | Localization of vasopressin-, vasoactive intestinal polypeptide-, peptide histidine isoleucine- and somatostatin-mRNA in rat suprachiasmatic nucleus. | Card JP et al |
| 8873894 | 1996 | Regulation of VIP gene expression in general. Human lung cancer cells in particular. | Davidson A et al |
| 19859678 | 2010 | VIP and PACAP. | Fahrenkrug J et al |
| 17430175 | 2007 | Therapeutical approaches of vasoactive intestinal peptide as a pleiotropic immunomodulator. | Gonzalez-Rey E et al |
| 2909364 | 1989 | Lactation elevates vasoactive intestinal peptide messenger ribonucleic acid in rat suprachiasmatic nucleus. | Gozes I et al |
| 17003842 | 2007 | Vasoactive intestinal peptide gene alterations in patients with idiopathic pulmonary arterial hypertension. | Haberl I et al |
| 22289055 | 2012 | Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1. | Harmar AJ et al |
| 11121793 | 2001 | Vasoactive intestinal peptide: cardiovascular effects. | Henning RJ et al |
| 2544928 | 1989 | Promotion of differentiation in human colon carcinoma cells by vasoactive intestinal polypeptide. | Hoosein NM et al |
| 1255530 | 1976 | Comparison of vasoactive intestinal peptide and secretin in stimulation of pancreatic secretion. | Konturek SJ et al |
| 6786616 | 1981 | Clinicopathological study of pancreatic and ganglioneuroblastoma tumours secreting vasoactive intestinal polypeptide (vipomas). | Long RG et al |
| 3123488 | 1988 | Vasoactive intestinal polypeptide and muscarine mobilize intracellular Ca2+ through breakdown of phosphoinositides to induce catecholamine secretion. Role of IP3 in exocytosis. | Malhotra RK et al |
| 7606249 | 1995 | Estradiol induces vasoactive intestinal peptide and prolactin gene expression in the rat anterior pituitary independently of plasma prolactin levels. | Montagne MN et al |
| 12570813 | 2003 | Neuropeptides as autocrine growth factors in cancer cells. | Moody TW et al |
| 17430173 | 2007 | Vasoactive intestinal peptide receptors: a molecular target in breast and lung cancer. | Moody TW et al |
| 21157320 | 2011 | VIP and PACAP: recent insights into their functions/roles in physiology and disease from molecular and genetic studies. | Moody TW et al |
| 17580098 | 2007 | Vasoactive intestinal peptide-camptothecin conjugates inhibit the proliferation of breast cancer cells. | Moody TW et al |
| 8389448 | 1993 | A vasoactive intestinal peptide antagonist inhibits non-small cell lung cancer growth. | Moody TW et al |
| 2960611 | 1987 | Selective effects of vasoactive intestinal peptide on the mitogenic response of murine T cells. | Ottaway CA et al |
| 21524251 | 2011 | VIP-induced neuroprotection of the developing brain. | Passemard S et al |
| 9662242 | 1998 | 123I-labelled vasoactive intestinal peptide receptor scintigraphy in patients with colorectal cancer. | Raderer M et al |
| 2898911 | 1988 | Neuroendocrine significance of vasoactive intestinal polypeptide. | Reichlin S et al |
| 10850463 | 2000 | Vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide receptor subtypes in human tumors and their tissues of origin. | Reubi JC et al |
| 20356986 | 2010 | Asthma and pulmonary arterial hypertension: do they share a key mechanism of pathogenesis? | Said SI et al |
| 5450698 | 1970 | Polypeptide with broad biological activity: isolation from small intestine. | Said SI et al |
| 15223046 | 2004 | The multiple mediators of neurogenic smooth muscle relaxation. | Said SI et al |
| 3291690 | 1988 | Vasoactive intestinal peptide in the peripheral nervous system. | Sundler F et al |
| 23700405 | 2013 | VIP gene deletion in mice causes cardiomyopathy associated with upregulation of heart failure genes. | Szema AM et al |
| 13571250 | 1958 | Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia. | VERNER JV et al |
| 22728770 | 2012 | Vasoactive intestinal peptide (VIP) inhibits human renal cell carcinoma proliferation. | Vacas E et al |
| 19101605 | 2009 | Vasoactive intestinal peptide (VIP) induces transactivation of EGFR and HER2 in human breast cancer cells. | Valdehita A et al |
| 19805477 | 2009 | Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. | Vaudry D et al |
| 19508420 | 2009 | VIP gene variants related to idiopathic pulmonary arterial hypertension in Chinese population. | Zhang Y et al |
Other Information
Locus ID:
NCBI: 7432
MIM: 192320
HGNC: 12693
Ensembl: ENSG00000146469
Variants:
dbSNP: 7432
ClinVar: 7432
TCGA: ENSG00000146469
COSMIC: VIP
RNA/Proteins
| Gene ID | Transcript ID | Uniprot |
|---|---|---|
| ENSG00000146469 | ENST00000367243 | P01282 |
| ENSG00000146469 | ENST00000367244 | P01282 |
| ENSG00000146469 | ENST00000431366 | H0Y763 |
Expression (GTEx)
Pathways
| Pathway | Source | External ID |
|---|---|---|
| Signal Transduction | REACTOME | R-HSA-162582 |
| Signaling by GPCR | REACTOME | R-HSA-372790 |
| GPCR downstream signaling | REACTOME | R-HSA-388396 |
| G alpha (s) signalling events | REACTOME | R-HSA-418555 |
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 38674298 | 2024 | Effects of the Neuropeptides Pituitary Adenylate Cyclase Activating Polypeptide and Vasoactive Intestinal Peptide in Male Fertility. | 0 |
| 38674298 | 2024 | Effects of the Neuropeptides Pituitary Adenylate Cyclase Activating Polypeptide and Vasoactive Intestinal Peptide in Male Fertility. | 0 |
| 36768369 | 2023 | Sympathetic System in Wound Healing: Multistage Control in Normal and Diabetic Skin. | 4 |
| 36768369 | 2023 | Sympathetic System in Wound Healing: Multistage Control in Normal and Diabetic Skin. | 4 |
| 34698942 | 2022 | Significance of serum VIP and PACAP in multiple sclerosis: an exploratory case-control study. | 5 |
| 35216459 | 2022 | Human CD4(+)CD45RA(+) T Cells Behavior after In Vitro Activation: Modulatory Role of Vasoactive Intestinal Peptide. | 0 |
| 35443019 | 2022 | Donor plasmacytoid dendritic cells limit graft-versus-host disease through vasoactive intestinal polypeptide expression. | 5 |
| 34698942 | 2022 | Significance of serum VIP and PACAP in multiple sclerosis: an exploratory case-control study. | 5 |
| 35216459 | 2022 | Human CD4(+)CD45RA(+) T Cells Behavior after In Vitro Activation: Modulatory Role of Vasoactive Intestinal Peptide. | 0 |
| 35443019 | 2022 | Donor plasmacytoid dendritic cells limit graft-versus-host disease through vasoactive intestinal polypeptide expression. | 5 |
| 33502586 | 2021 | VIP modulates human macrophages phenotype via FPRL1 via activation of RhoA-GTPase and PLC pathways. | 1 |
| 34146741 | 2021 | Changes in ghrelin, substance P and vasoactive intestinal peptide levels in the gastroduodenal mucosa of patients with morbid obesity. | 4 |
| 33502586 | 2021 | VIP modulates human macrophages phenotype via FPRL1 via activation of RhoA-GTPase and PLC pathways. | 1 |
| 34146741 | 2021 | Changes in ghrelin, substance P and vasoactive intestinal peptide levels in the gastroduodenal mucosa of patients with morbid obesity. | 4 |
| 33361631 | 2020 | Vasopressin in circadian function of SCN. | 5 |
Citation
Terry Moody
VIP (vasoactive intestinal peptide)
Atlas Genet Cytogenet Oncol Haematol. 2013-08-01
Online version: http://atlasgeneticsoncology.org/gene/44215/vip-%28vasoactive-intestinal-peptide%29
