STRAP

For other uses, see STRAP (disambiguation).

STRAP
Identifiers
Aliases	STRAP, MAWD, PT-WD, UNRIP, serine/threonine kinase receptor associated protein
External IDs	OMIM: 605986; MGI: 1329037; GeneCards: STRAP
Gene location (Human) Chr. Chromosome 12 (human) Band 12p12.3 Start 15,882,387 bp End 15,903,478 bp
Gene location (Mouse) Chr. Chromosome 6 (mouse) Band 6|6 G1 Start 137,712,076 bp End 137,728,930 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in secondary oocyte corpus epididymis pons tail of epididymis beta cell caput epididymis anterior pituitary embryo ventricular zone ganglionic eminence Top expressed in mandibular prominence maxillary prominence somite seminiferous tubule cumulus cell abdominal wall epiblast primitive streak hair follicle ventricular zone More reference expression data BioGPS n/a
Gene ontology Molecular function signaling receptor binding protein binding RNA binding Cellular component cytoplasm SMN complex SMN-Sm protein complex cytosol nucleus nucleoplasm Biological process mRNA processing negative regulation of transcription by RNA polymerase II negative regulation of epithelial cell migration maintenance of gastrointestinal epithelium negative regulation of transforming growth factor beta receptor signaling pathway negative regulation of epithelial to mesenchymal transition negative regulation of pathway-restricted SMAD protein phosphorylation RNA splicing negative regulation of epithelial cell proliferation spliceosomal snRNP assembly Sources:Amigo / QuickGO
Orthologs Databases NCBI: entry; OMA: entry Species Human Mouse Entrez 11171 20901 Ensembl ENSG00000023734 ENSMUSG00000030224 UniProt Q9Y3F4 Q9Z1Z2 RefSeq (mRNA) NM_007178 NM_011499 RefSeq (protein) NP_009109 NP_035629 Location (UCSC) Chr 12: 15.88 – 15.9 Mb Chr 6: 137.71 – 137.73 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

The figure illustrates the inhibitory effect of NM23-H1 on Smad3 nuclear translocation in the TGF-β signaling pathway. Panels A and B show NM23-H1's impact on the association of activated TGF-β receptor with Smad7 and STRAP, respectively. Panels C and D demonstrate NM23-H1's modulation of Smad3 localization in Hep3B cells. Panel E extends this analysis with NM23-H1(C145S). Quantitative analysis, using densitometry, shows the relative Smad3 expression levels compared to controls. These experiments collectively highlight NM23-H1's role in regulating Smad3 and its association with TGF-β signaling components. The data are representative of multiple independent experiments.

Serine-threonine kinase receptor-associated protein is an protein that in humans is encoded by the STRAP gene.

Structure

STRAP is a 38.5 kDa, 350-amino acid protein belonging to the WD40 repeat protein family. It contains seven WD40 repeats that fold into a seven-bladed β-propeller structure that spans almost the entire length of the protein. The N-terminal WD40 repeats binds to TGF-β receptor I, whereas the C-terminal region is phosphorylated by TGF-β receptor II.

Function

STRAP is a WD40-repeat protein that binds both the type I and type II TGF-β receptors. Its primary function is to recruit and stabilize the inhibitory Smad, SMAD7, at the activated TGF-β receptor complex.

By stabilizing this STRAP/SMAD7/TGF-β receptor complex, STRAP sterically blocks SMAD2 and SMAD3 from binding to the activated type I TGF-β receptor, preventing its phosphorylation and thus blunting TGF-β mediated up-regulation of gene expression.

Apoptosis

STRAP binds directly to ASK1 through ASK1's C-terminal domain and the fourth and sixth WD40 repeats of STRAP. This binding allows STRAP to be phosphorylated by ASK1, and the resulting complex reduces ASK1's downstream signaling to the JNK and p38 stress-response pathways. It does so by helping to stabilize ASK1's association with its own inhibitory proteins, thioredoxin and 14-3-3. It also reduces ASK1's ability to form a complex with its downstream target MKK3. Through this mechanism, STRAP protects cells from H₂O₂-induced, ASK1-driven apoptosis, favoring cell survival. STRAP has also been described as a positive regulator of PDK1 signaling.

Clinical significance

STRAP is a component of the survival motor neuron (SMN) complex, binding to it through an interaction with GEMIN7. Loss of the complex's core protein, SMN, causes spinal muscular atrophy, a childhood disorder characterized by motor neuron degeneration.

STRAP also inhibits TGF-β receptor signaling by stabilizing the inhibitory protein SMAD7, which in turn limits activation of SMAD2 and SMAD3. This pathway is frequently dysregulated in cancer and elevated STRAP expression has been reported in several tumor types, including colorectal and lung carcinoma, where it promotes proliferation and reduces apoptosis.

Interactions

STRAP has been shown to interact with:

• Mothers against decapentaplegic homolog 2,
• Mothers against decapentaplegic homolog 3,
• Mothers against decapentaplegic homolog 6,
• Mothers against decapentaplegic homolog 7,
• TGF beta receptor 1, and
• TGF beta receptor 2.

Further reading

• Hunt SL, Hsuan JJ, Totty N, Jackson RJ (February 1999). "unr, a cellular cytoplasmic RNA-binding protein with five cold-shock domains, is required for internal initiation of translation of human rhinovirus RNA". Genes & Development. 13 (4): 437–448. doi:10.1101/gad.13.4.437. PMC 316477. PMID 10049359.
• Matsuda S, Katsumata R, Okuda T, Yamamoto T, Miyazaki K, Senga T, et al. (January 2000). "Molecular cloning and characterization of human MAWD, a novel protein containing WD-40 repeats frequently overexpressed in breast cancer". Cancer Research. 60 (1): 13–17. PMID 10646843.
• Zhang QH, Ye M, Wu XY, Ren SX, Zhao M, Zhao CJ, et al. (October 2000). "Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells". Genome Research. 10 (10): 1546–1560. doi:10.1101/gr.140200. PMC 310934. PMID 11042152.
• Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, et al. (March 2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs". Genome Research. 11 (3): 422–435. doi:10.1101/gr.GR1547R. PMC 311072. PMID 11230166.
• Iriyama C, Matsuda S, Katsumata R, Hamaguchi M (2001). "Cloning and sequencing of a novel human gene which encodes a putative hydroxylase". Journal of Human Genetics. 46 (5): 289–292. doi:10.1007/s100380170081. PMID 11355021.
• Pillai RS, Grimmler M, Meister G, Will CL, Lührmann R, Fischer U, et al. (September 2003). "Unique Sm core structure of U7 snRNPs: assembly by a specialized SMN complex and the role of a new component, Lsm11, in histone RNA processing". Genes & Development. 17 (18): 2321–2333. doi:10.1101/gad.274403. PMC 196468. PMID 12975319.
• Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y, Wrana JL (March 2005). "Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity". Science. 307 (5715). New York, N.Y.: 1603–1609. Bibcode:2005Sci...307.1603O. doi:10.1126/science.1105718. PMID 15761148. S2CID 41013935.
• Barrios-Rodiles M, Brown KR, Ozdamar B, Bose R, Liu Z, Donovan RS, et al. (March 2005). "High-throughput mapping of a dynamic signaling network in mammalian cells". Science. 307 (5715). New York, N.Y.: 1621–1625. Bibcode:2005Sci...307.1621B. doi:10.1126/science.1105776. PMID 15761153. S2CID 39457788.
• Carissimi C, Baccon J, Straccia M, Chiarella P, Maiolica A, Sawyer A, et al. (April 2005). "Unrip is a component of SMN complexes active in snRNP assembly". FEBS Letters. 579 (11): 2348–2354. Bibcode:2005FEBSL.579.2348C. doi:10.1016/j.febslet.2005.03.034. PMID 15848170. S2CID 10276186.
• Grimmler M, Otter S, Peter C, Müller F, Chari A, Fischer U (October 2005). "Unrip, a factor implicated in cap-independent translation, associates with the cytosolic SMN complex and influences its intracellular localization". Human Molecular Genetics. 14 (20): 3099–3111. doi:10.1093/hmg/ddi343. PMID 16159890.
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, et al. (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–1178. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.
• Guo D, Han J, Adam BL, Colburn NH, Wang MH, Dong Z, et al. (December 2005). "Proteomic analysis of SUMO4 substrates in HEK293 cells under serum starvation-induced stress". Biochemical and Biophysical Research Communications. 337 (4): 1308–1318. Bibcode:2005BBRC..337.1308G. doi:10.1016/j.bbrc.2005.09.191. PMID 16236267.
• Seong HA, Jung H, Choi HS, Kim KT, Ha H (December 2005). "Regulation of transforming growth factor-beta signaling and PDK1 kinase activity by physical interaction between PDK1 and serine-threonine kinase receptor-associated protein". The Journal of Biological Chemistry. 280 (52): 42897–42908. doi:10.1074/jbc.M507539200. PMID 16251192.
• Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, et al. (January 2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Research. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.
• Carissimi C, Saieva L, Gabanella F, Pellizzoni L (December 2006). "Gemin8 is required for the architecture and function of the survival motor neuron complex". The Journal of Biological Chemistry. 281 (48): 37009–37016. doi:10.1074/jbc.M607505200. PMID 17023415.