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MACF1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4Z6G
Identifiers
Aliases	MACF1, ABP620, ACF7, MACF, OFC4, microtubule-actin crosslinking factor 1, LIS9, microtubule actin crosslinking factor 1, Lnc-PMIF
External IDs	OMIM: 608271; MGI: 108559; HomoloGene: 136220; GeneCards: MACF1; OMA:MACF1 - orthologs
Gene location (Human) Chr. Chromosome 1 (human) Band 1p34.3 Start 39,081,316 bp End 39,487,177 bp
Gene location (Mouse) Chr. Chromosome 4 (mouse) Band 4 D2.2|4 57.42 cM Start 123,349,633 bp End 123,684,360 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in inferior olivary nucleus dorsal motor nucleus of vagus nerve right lung Achilles tendon epithelium of colon corpus callosum middle temporal gyrus saphenous vein upper lobe of left lung ventricular zone Top expressed in left lung lobe paraventricular nucleus of hypothalamus mammillary body right lung superior colliculus ventromedial nucleus arcuate nucleus right lung lobe cerebellar vermis ventral tegmental area More reference expression data BioGPS More reference expression data
Gene ontology Molecular function metal ion binding calcium ion binding actin binding microtubule binding protein binding RNA binding cadherin binding ATPase activity microtubule minus-end binding actin filament binding structural molecule activity cytoskeletal protein binding Cellular component Golgi apparatus cell projection membrane microtubule ruffle membrane plasma membrane cytoskeleton cytoplasm intermediate filament actin cytoskeleton Biological process Wnt signaling pathway Golgi to plasma membrane protein transport wound healing positive regulation of axon extension regulation of microtubule-based process regulation of epithelial cell migration positive regulation of Wnt signaling pathway regulation of cell migration regulation of focal adhesion assembly cytoskeleton organization intermediate filament cytoskeleton organization Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 23499 11426 Ensembl ENSG00000127603 ENSMUSG00000028649 UniProt Q9UPN3 Q9QXZ0 RefSeq (mRNA) NM_012090 NM_033044 NM_001394062 NM_001199136 NM_001199137 NM_009600 RefSeq (protein) NP_036222 n/a Location (UCSC) Chr 1: 39.08 – 39.49 Mb Chr 4: 123.35 – 123.68 Mb PubMed search
Wikidata
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Microtubule-actin cross-linking factor 1, isoforms 1/2/3/5 is a protein that in humans is encoded by the MACF1 gene.

MACF1 encodes a large protein containing numerous spectrin and leucine-rich repeat (LRR) domains. MACF1 is a member of a family of proteins that form bridges between different cytoskeletal elements. This protein facilitates actin-microtubule interactions at the cell periphery and couples the microtubule network to cellular junctions.

MACF1 belongs to a subset of +TIPs or proteins which bind to growing microtubule ends called spectraplakins. Spectraplakins characteristically have distinctive microtubule and actin binding domains, which allow MACF1 to bind to both cytoskeletal elements. MACF1 goes by many names and is also called ACF7 or actin cross-linking factor 7, MACF, macrophin, trabeculin α, and ABP620. Alternatively spliced transcript variants encoding distinct isoforms of MACF1 have been described. MACF1 is also an important protein for cell migration in processes such as wound healing.

Structure

MACF1 is an enormous protein of 5380 amino acid residues. The N-terminal segment has an actin binding domain and the C-terminal segment has a +TIP binding site as well as microtubule interacting domains. This allows MACF1 to crosslink both actin and microtubules. The C-terminal region contains both a Gas2-related domain and a GSR-repeat domain, which both are involved with interacting with microtubules. The C-terminus of MACF1 is thought to associate to the microtubule lattice through the acidic C-terminal tails of tubulin subunits. However, MACF1 does not always associate with the microtubule directly, and also binds through many proteins which localize at the microtubule plus end. Such proteins include EB1, CLASP1, and CLASP2, whose interactions with MACF1 were determined through coimmunoprecipitation assay. Not only does MACF1's C-terminal tail bind to microtubules, but it also has key phosphorylation sites. When these sites are phosphorylated by its regulator GSK3β, the ability of MACF1 to bind to microtubules is disrupted. MACF1 also has an actin-regulated ATPase domain, which is approximately 3000 amino acid residues long in the C-terminal region, and is responsible for cytoskeletal dynamics.

Function

Embryonic development

MACF1 is important for embryonic development. For mice, by embryonic day 7.5 (E7.5), MACF1 is expressed in the headfold and primitive streak, and by E8.5 the protein is expressed in neuronal tissues and the foregut. MACF1 was shown to be present in the Wnt signaling pathway. When Wnt signalling is not present, MACF1 associates with a complex containing axin, β-catenin, GSK3β, and APC. However, upon Wnt signaling, MACF1 is involved in a translation and binding of the axin complex to LTP6 at the cell membrane. Also, MACF1 is required for sufficient β-catenin to travel to the nucleus, where subsequently TCF/β-catenin-dependent transcriptional activation of a gene T encoding the protein brachyury occurs. Brachyury is an essential transcription factor required for mesoderm formation. Without MACF1, insufficient brachyury is transcribed, and hence, the mesoderm does not form. In fact, MACF1 knock-out mice, which lack the protein, show clear developmental retardation by E7.5, and eventually die at gastrulation due to defects in the formation of the primitive streak, node, and mesoderm.

Cell migration

Mice with conditional knock-outs in MACF1 in hair follicle stem cells have defects in cell migration. The focal adhesions in cells lacking MACF1 associate with cables of F-actin, causing cell migration to stall. Wild-type cells with MACF1 present have coordinated cytoskeletal dynamics, which allow for proper cell migration. MACF1 plays an important role in microtubule organization, and without MACF1, microtubules in migrating cells are bending and curly, instead of straight and radial. When wounded, conditional knock-outs for MACF1 have around a 40% delay in migration over 4 to 6 days after injury compared to the wild-type controls, showing that MACF1 plays an important role in cell migration. There are suggestions that imply that MACF1 may play a role in golgi polarization.

The major known regulator of MACF1 is GSK3β, which when uninhibited phosphorylates MACF1 among its many other substrates and uncouples MACF1 from microtubules. The phosphorylation of MACF1 occurs in the GSR domain, which is involved in microtubule binding, and has 32% of the amino acid residues are serines or threonines. MACF1 has 6 serines, which are possible GSK3β phosphorylation sites. GSK3β activity is high in non-stimulated cells, but during cell migration its activity is dampened along the cell leading edge.

In vivo, GSK3β activity is inhibited by Wnt signalling, but in vitro it is typically inhibited by cdc42. Extracellular Wnt signalling acts on the Frizzled receptor on the cellular membrane, which then, through a signalling cascade inhibits GSK3β. The inhibition of GSK3β creates a gradient at the leading edge, allowing MACF1 to remain active and unphosphorylated, so that it can form necessary connections between microtubules and actin so migration can occur. It was found in hair follicle stem cells that phosphorylation-refractile MACF1 rescues microtubule architecture from a MACF1 knock-out, whereas phosphorylation-constitutive MACF1 is unable to rescue the phenotype. However, neither phosphorylation-refractile MACF1 nor phosphorylation-constitutive MACF1 are able to rescue polarized cell movement. This implies that the phospho-regulation dynamics permitted in the wild type MACF1 are necessary for polarized cell movement to take place.

Clinical significance

In breast carcinoma cells, addition of heregulin β activates ErbB2, a receptor tyrosine, which causes microtubules to form many cell protrusions to cause cell motility. ErbB2 controls microtubule outgrowth and stabilization at the cell cortex through a specific pathway. When GSK3β is active, APC and CLASP2 are sequentially inactivated by the kinase, which gives a condition where microtubule formation is not favoured at the front of the cell. For cell migration to occur, a mechanism is needed to decrease the activity of GSK3β to promote growth of microtubules. First, ErbB2 recruits Memo (mediator of ErbB2-driven motility) to the plasma membrane, which then promotes the phosphorylation of GSK3β on serine 9. This decreases the amount of GSK3β activity, and permits the localization of APC and CLASP2 to the cell membrane, which are both microtubule +TIPs. Although CLASP2 is present at the cell membrane, it appears to have a separate, independent mechanism for microtubule growth than APC. When ErbB2 inactivates GSK3β, APC localizes to the membrane and is then able to recruit MACF1 to the membrane as well. The APC-mediated recruitment of MACF1 to the membrane is required and sufficient for microtubule capture and stabilization at the cell cortex during breast carcinoma cell motility.

References

1. ^ GRCh38: Ensembl release 89: ENSG00000127603 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000028649 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Byers TJ, Beggs AH, McNally EM, Kunkel LM (Sep 1995). "Novel actin crosslinker superfamily member identified by a two step degenerate PCR procedure". FEBS Lett. 368 (3): 500–4. doi:10.1016/0014-5793(95)00722-L. PMID 7635207.
6. Okuda T, Matsuda S, Nakatsugawa S, Ichigotani Y, Iwahashi N, Takahashi M, Ishigaki T, Hamaguchi M (Dec 1999). "Molecular cloning of macrophin, a human homologue of Drosophila kakapo with a close structural similarity to plectin and dystrophin". Biochem Biophys Res Commun. 264 (2): 568–74. doi:10.1006/bbrc.1999.1538. PMID 10529403.
7. ^ "Entrez Gene: MACF1 microtubule-actin crosslinking factor 1".
8. Kumar P, Wittmann T (2012). "+TIPs: SxIPping along microtubule ends". Trends Cell Biol. 22 (8): 418–28. doi:10.1016/j.tcb.2012.05.005. PMC 3408562. PMID 22748381.
9. ^ Kodama A, Karakesisoglou I, Wong E, Vaezi A, Fuchs E (2003). "ACF7: An Essential Integrator of Microtubule Dynamics". Cell. 115 (3): 343–54. doi:10.1016/S0092-8674(03)00813-4. PMID 14636561. S2CID 5249501.
10. Röper K, Gregory SL, Brown NH (2002). "The 'spectraplakins': cytoskeletal giants with characteristics of both spectrin and plakin families". J. Cell Sci. 115 (Pt 22): 4215–25. doi:10.1242/jcs.00157. hdl:2440/41876. PMID 12376554.
11. Yucel G, Oro AE (2011). "Cell Migration: GSK3beta Steers the Cytoskeleton's Tip". Cell. 144 (3): 319–21. doi:10.1016/j.cell.2011.01.023. PMC 3929416. PMID 21295692.
12. ^ Wu X, Shen QT, Oristian DS, Lu CP, Zheng Q, Wang HW, Fuchs E (Feb 4, 2011). "Skin Stem Cells Orchestrate Directional Migration by Regulating Microtubule-ACF7 Connections through GSK3beta". Cell. 144 (3): 341–52. doi:10.1016/j.cell.2010.12.033. PMC 3050560. PMID 21295697.
13. ^ Wu X, Kodama A, Fuchs E (2008). "ACF7 regulates cytoskeletal-focal adhesion dynamics and migration and has ATPase activity". Cell. 135 (1): 137–48. doi:10.1016/j.cell.2008.07.045. PMC 2703712. PMID 18854161.
14. Chen HJ, Lin CM, Lin CS, Perez-Olle R, Leung CL, Liem RK (Jul 2006). "The role of microtubule actin cross-linking factor 1 (MACF1) in the Wnt signaling pathway". Genes Dev. 20 (14): 1933–45. doi:10.1101/gad.1411206. PMC 1522081. PMID 16815997.
15. Zaoui K, Benseddik K, Daou P, Salaün D, Badache A (2010). "ErbB2 receptor controls microtubule capture by recruiting MACF1 to the plasma membrane of migrating cells". PNAS. 107 (43): 18517–22. Bibcode:2010PNAS..10718517Z. doi:10.1073/pnas.1000975107. PMC 2972954. PMID 20937854.

Further reading

• Nakajima D, Okazaki N, Yamakawa H, Kikuno R, Ohara O, Nagase T (2003). "Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones". DNA Res. 9 (3): 99–106. doi:10.1093/dnares/9.3.99. PMID 12168954.
• Caccamise DA (1978). "My franchise was a teen-age lion's den". Dental Economics – Oral Hygiene. 66 (11): 36–43. PMID 1074709.
• Seki N, Ohira M, Nagase T, Ishikawa K, Miyajima N, Nakajima D, Nomura N, Ohara O (1998). "Characterization of cDNA clones in size-fractionated cDNA libraries from human brain". DNA Res. 4 (5): 345–9. doi:10.1093/dnares/4.5.345. PMID 9455484.
• Sun Y, Zhang J, Kraeft SK, Auclair D, Chang MS, Liu Y, Sutherland R, Salgia R, Griffin JD, Ferland LH, Chen LB (1999). "Molecular cloning and characterization of human trabeculin-alpha, a giant protein defining a new family of actin-binding proteins". J. Biol. Chem. 274 (47): 33522–30. doi:10.1074/jbc.274.47.33522. PMID 10559237.
• Nagase T, Ishikawa K, Kikuno R, Hirosawa M, Nomura N, Ohara O (2000). "Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro". DNA Res. 6 (5): 337–45. doi:10.1093/dnares/6.5.337. PMID 10574462.
• Leung CL, Sun D, Zheng M, Knowles DR, Liem RK (2000). "Microtubule actin cross-linking factor (MACF): a hybrid of dystonin and dystrophin that can interact with the actin and microtubule cytoskeletons". J. Cell Biol. 147 (6): 1275–86. doi:10.1083/jcb.147.6.1275. PMC 2168091. PMID 10601340.
• Karakesisoglou I, Yang Y, Fuchs E (2000). "An epidermal plakin that integrates actin and microtubule networks at cellular junctions". J. Cell Biol. 149 (1): 195–208. doi:10.1083/jcb.149.1.195. PMC 2175090. PMID 10747097.
• Sun D, Leung CL, Liem RK (2001). "Characterization of the microtubule binding domain of microtubule actin crosslinking factor (MACF): identification of a novel group of microtubule associated proteins". J. Cell Sci. 114 (Pt 1): 161–172. doi:10.1242/jcs.114.1.161. PMID 11112700.
• Gong TW, Besirli CG, Lomax MI (2002). "MACF1 gene structure: a hybrid of plectin and dystrophin". Mamm. Genome. 12 (11): 852–61. CiteSeerX 10.1.1.495.6352. doi:10.1007/s00335-001-3037-3. PMID 11845288. S2CID 8121128.
• Nakayama M, Kikuno R, Ohara O (2003). "Protein-protein interactions between large proteins: two-hybrid screening using a functionally classified library composed of long cDNAs". Genome Res. 12 (11): 1773–84. doi:10.1101/gr.406902. PMC 187542. PMID 12421765.
• Kodama A, Karakesisoglou I, Wong E, Vaezi A, Fuchs E (2004). "ACF7: an essential integrator of microtubule dynamics". Cell. 115 (3): 343–54. doi:10.1016/S0092-8674(03)00813-4. PMID 14636561. S2CID 5249501.
• Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM (2004). "Functional proteomics mapping of a human signaling pathway". Genome Res. 14 (7): 1324–32. doi:10.1101/gr.2334104. PMC 442148. PMID 15231748.
• Kakinuma T, Ichikawa H, Tsukada Y, Nakamura T, Toh BH (2004). "Interaction between p230 and MACF1 is associated with transport of a glycosyl phosphatidyl inositol-anchored protein from the Golgi to the cell periphery". Exp. Cell Res. 298 (2): 388–98. doi:10.1016/j.yexcr.2004.04.047. PMID 15265687.
• Lin CM, Chen HJ, Leung CL, Parry DA, Liem RK (2006). "Microtubule actin crosslinking factor 1b: a novel plakin that localizes to the Golgi complex". J. Cell Sci. 118 (Pt 16): 3727–38. doi:10.1242/jcs.02510. PMID 16076900.
• Gevaert K, Staes A, Van Damme J, De Groot S, Hugelier K, Demol H, Martens L, Goethals M, Vandekerckhove J (2006). "Global phosphoproteome analysis on human HepG2 hepatocytes using reversed-phase diagonal LC". Proteomics. 5 (14): 3589–99. doi:10.1002/pmic.200401217. PMID 16097034. S2CID 895879.

• Genes on human chromosome 1
• EF-hand-containing proteins
• Plakins