Pathway Human Homo sapiens

Insulin processing

R-HSA-264876 in Reactome release 97: under Peptide hormone metabolism, with 25 genes placed in it by the mapping files and 0 child pathways in the hierarchy.

The same number in the other species

Reactome writes the mouse and rat events it infers from a human pathway under the human number with the species token. A door opens only where that species' own list in this release holds the id: R-MMU-264876 (mouse), R-RNO-264876 (rat). Whether the event was inferred from this one is what the record says.

The record
The genes
Parents and children

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This page reads the pathway's record from its source while you read the rest; with scripts off the card stays at its loading line. Reload with scripts on to see it, or open the source's own page from the link in the card.

01The record

Reactome's own record of this pathway

What this tells you

The pathway list, the hierarchy and the genes on this page are read from the files Reactome publishes for Reactome release 97, built into this site on 2026-09-09: the pathway list, the hierarchy relationship file and the two gene mapping files. The record card is the one live read, Reactome's own record of this pathway.

Reactome's download page describes the mapping files: Mapping files link the source database identifier to the lowest level pathway diagram or subset of the pathway, all levels of the pathway hierarchy or database identifier to all reactions. [R13] The gene list here is the all-levels mapping of NCBI Gene ids, filled from the all-levels mapping of Ensembl ids where the NCBI file has no row for a gene; each row names which file it came from by the shape of its source id. Each row carries the evidence codes the file writes for it, as written and unranked, and both where the file writes both; no page of Reactome's documentation the survey read defines the codes, so this page does not expand them. A gene id the identity files do not name is kept as the source's own id with no door rather than turned into a symbol.

On citing what a search finds, Reactome says: It should be remembered that while we strive to contain the most current and accurate data, Reactome should not be used in citations where other primary sources of information are available. [R12] The record card prints the literature Reactome attaches to a curated pathway for that reason. The data are public domain: All data in the Reactome database and files derived from that data are licensed under the Creative Commons Public Domain Dedication (CC0). User may copy, modify, and distribute these data, even for commercial purposes, without asking for permission. Attribution is encouraged but not required. [R10] The pathway illustrations are licensed apart, under CC BY 4.0, and none is shown here.

A gene on this list is one Reactome places in this pathway in this release, and that is all the row says: it does not say the gene is expressed in a tissue or associated with a disease, which are the other two explorers' questions, read from other sources. Reactome's papers of record are [R01] [R02].

[R01] Ragueneau E, Gong C, Sinquin P, Sevilla C, Beavers D, Grentner A, et al. (2026). The Reactome Knowledgebase 2026. Nucleic Acids Research 54:D673-D681. PMID 41251150, doi 10.1093/nar/gkaf1223.
[R02] Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. (2024). The Reactome Pathway Knowledgebase 2024. Nucleic Acids Research 52:D672-D678. PMID 37941124, doi 10.1093/nar/gkad1025.
[R10] Reactome, reactome.org. License Agreement. https://reactome.org/license, read 2026-09-09.
[R12] Reactome, reactome.org. Citing us. https://reactome.org/cite, read 2026-09-09.
[R13] Reactome, reactome.org. Download. https://reactome.org/download-data, read 2026-09-09.

Stable id: R-HSA-264876.7
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2008-12-17
Last updated: 2022-12-07
Events inside: 17, counted from the record

Generation of insulin containing secretory granules from newly synthesized proinsulin in the lumen of the endoplasmic reticulum (ER) involves formation of proinsulin intramolecular disulfide bonds, formation of proinsulin zinc calcium complexes, proteolytic cleavage of proinsulin to yield insulin and C peptide, and translocation of the granules across the cytosol to the plasma membrane (Dodson & Steiner 1998).

Transcription of the human insulin gene INS is annotated as part of the pathway “Regulation of gene expression in beta cells” (see reaction R-HSA-211289). The preproinsulin mRNA is translated by ribosomes at the rough endoplasmic reticulum (ER) and the preproinsulin enters the secretion pathway by virtue of its signal peptide, which is co-translationally cleaved to yield proinsulin.

In the process annotated here, within the ER, three intramolecular disulfide bonds form in proinsulin, mediated by P4HD (PDI1A) and ERO1B proteins. Correctly folded, disulfide-bonded proinsulin then moves via vesicles from the ER to the Golgi Complex where it forms complexes with zinc and calcium.

Proinsulin zinc calcium complexes bud in vesicles from the trans Golgi to form immature secretory vesicles (secretory granules) in the cytosol. Within the immature granules, endoproteases PCKS1 and PCKS2 (Prohormone Convertases 1 and 2) cleave proinsulin at two sites and CPE (Carboxypeptidase E) removes additional amino acid residues to yield the cystine bonded A and B chains of mature insulin and the C peptide, which will be secreted with the insulin. The insulin zinc calcium complexes form insoluble crystals within the granule.

The insulin containing secretory granules are then translocated across the cytosol to the inner surface of the plasma membrane. Translocation occurs initially by attachment of the granules to Kinesin 1, which motors along microtubules, and then by attachment to Myosin Va, which motors along the microfilaments of the cortical actin network.

A pancreatic beta cell contains about 10,000 insulin granules of which about 1,000 are docked at the plasma membrane and 50 are readily releasable in immediate response to stimulation by glucose or other secretogogues. Docking is due to interaction between the Exocyst proteins EXOC3 on the granule membrane and EXOC4 on the plasma membrane. Exocytosis is accomplished by interaction between SNARE type proteins Syntaxin 1A and Syntaxin 4 on the plasma membrane and Synaptobrevin 2/VAMP2 on the granule membrane. Exocytosis is a calcium dependent process due to interaction of the calcium binding membrane protein Synaptotagmin V/IX with the SNARE type proteins.

Reading this pathway's record from Reactome (the pathway record).Still reading. A first read of a pathway can take a while; this page waits up to 35 seconds for it, and its scripts then bring in the panel, or a line saying what did not arrive.

02The genes

Genes Reactome places in this human pathway

The mapping files place 25 genes in this human pathway; showing 1 to 25, in pages of 100, sorted by symbol for reading. The order carries no ranking.

Genes Reactome places in this human pathway, page 1 of 1
Gene	Authority id	Mapping file id	Evidence codes
GeneCLTRN	AuthorityHGNC:29437	Mapping file id57393 NCBI file	EvidenceIEA
GeneCPE	AuthorityHGNC:2303	Mapping file id1363 NCBI file	EvidenceIEA
GeneERO1B	AuthorityHGNC:14355	Mapping file id56605 NCBI file	EvidenceTAS
GeneEXOC1	AuthorityHGNC:30380	Mapping file id55763 NCBI file	EvidenceTAS
GeneEXOC2	AuthorityHGNC:24968	Mapping file id55770 NCBI file	EvidenceTAS
GeneEXOC3	AuthorityHGNC:30378	Mapping file id11336 NCBI file	EvidenceTAS
GeneEXOC4	AuthorityHGNC:30389	Mapping file id60412 NCBI file	EvidenceTAS
GeneEXOC5	AuthorityHGNC:10696	Mapping file id10640 NCBI file	EvidenceTAS
GeneEXOC6	AuthorityHGNC:23196	Mapping file id54536 NCBI file	EvidenceTAS
GeneEXOC7	AuthorityHGNC:23214	Mapping file id23265 NCBI file	EvidenceTAS
GeneEXOC8	AuthorityHGNC:24659	Mapping file id149371 NCBI file	EvidenceTAS
GeneINS	AuthorityHGNC:6081	Mapping file id3630 NCBI file	EvidenceIEA, TAS
GeneKIF5A	AuthorityHGNC:6323	Mapping file id3798 NCBI file	EvidenceIEA
GeneKIF5B	AuthorityHGNC:6324	Mapping file id3799 NCBI file	EvidenceIEA
GeneKIF5C	AuthorityHGNC:6325	Mapping file id3800 NCBI file	EvidenceIEA
GeneMYO5A	AuthorityHGNC:7602	Mapping file id4644 NCBI file	EvidenceIEA
GeneMYRIP	AuthorityHGNC:19156	Mapping file id25924 NCBI file	EvidenceIEA
GeneP4HB	AuthorityHGNC:8548	Mapping file id5034 NCBI file	EvidenceTAS
GenePCSK1	AuthorityHGNC:8743	Mapping file id5122 NCBI file	EvidenceIEA
GenePCSK2	AuthorityHGNC:8744	Mapping file id5126 NCBI file	EvidenceIEA
GeneRAB27A	AuthorityHGNC:9766	Mapping file id5873 NCBI file	EvidenceIEA
GeneSLC30A5	AuthorityHGNC:19089	Mapping file id64924 NCBI file	EvidenceTAS
GeneSLC30A8	AuthorityHGNC:20303	Mapping file id169026 NCBI file	EvidenceTAS
GeneSTX1A	AuthorityHGNC:11433	Mapping file id6804 NCBI file	EvidenceIEA
GeneVAMP2	AuthorityHGNC:12643	Mapping file id6844 NCBI file	EvidenceIEA

Evidence codes on this page: IEA, TAS, as the mapping file writes them; a row carrying two was written twice by the file, once under each. The mapping file id says which file placed the gene: an NCBI Gene id from NCBI2Reactome_All_Levels.txt, an Ensembl gene id from Ensembl2Reactome_All_Levels.txt. The two files can disagree about a code, so a row's codes are the one file's view. Measured by this site's build over this release on 2026-09-09: of the 138,908 human pathway-gene pairs both files place, 207 (0.149 per cent, over 47 genes) carry TAS in the Ensembl file where the NCBI rows carry IEA alone.

Reactome mapping files, the human rows for this pathway · Reactome release 97 · read 2026-09-09 · Reactome downloads"NCBI2Reactome_All_Levels.txt" and "Ensembl2Reactome_All_Levels.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.

03The hierarchy

Parents and children in this release's hierarchy

Parents

Peptide hormone metabolismR-HSA-298073688 genes

Children

None: no pathway of this release's list names this one as a parent.

Reactome's hierarchy is a graph rather than a tree: a pathway can sit under more than one parent, and the gene counts are each pathway's own placements at every level under it, so a parent's count is not the sum of its children's.

Reactome, the human pathway list and hierarchy relationship file · Reactome release 97 · read 2026-09-09 · Reactome downloads"ReactomePathways.txt" and "ReactomePathwaysRelation.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.