MAP2 (microtubule-associated protein 2)

2011-08-01   Ashika Jayanthy , Vijayasaradhi Setaluri 

Department of Dermatology, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.

Identity

HGNC
LOCATION
2q34
LOCUSID
ALIAS
MAP-2,MAP2A,MAP2B,MAP2C
FUSION GENES

DNA/RNA

Atlas Image

Description

The DNA consists of three or four tandem repeats that code for 31 amino acid long residues.
The gene contains 15 exons and has a size of 310064 base pairs. Alternative splicing of this gene gives rise to a large variety of transcripts and isoforms.

Transcription

Four transcription variants have been characterized.
- MAP2 Isoform 5 (NM_001039538.1 --> NP_001034627.1): The difference in this isoform is characterized by the 5 UTR which results in the production of a longer protein when compared to isoform 2.
- MAP2 Isoform 1 (NM_002374.3 --> NP_002365.3): This isoform is thought to be the longest encoded and contains three alternative in-frame exons when compared to isoform 2. The tubulin binding and MAP2 projection domains are conserved.
- MAP2 Isoform 2 (NM_031845.2 --> NP_114033.2): This is the shortest transcript.
- MAP2 Isoform 4 (NM_031847.2 --> NP_114035.2): One alternate in-frame exon compared to isoform 2.

Variant 5mRNAGene
Exon StartEndLengthStartEndLength
112302301230230
223128050835468359550
32813456515599015605465
43464227720100720108377
5423713291229096229386291
6714827114254526254639114
78289057825670425678178
89069676227623127629262
99681138171280404280574171
1011391286148281534281681148
1112871627341285868286208341
12162817209329954929964193
131721180282*301633301744112*
1418031915113305804305916113
151916584439293061363100643929
TOTAL LENGTH : 5844*

Variant 1mRNAGene
ExonStartEndLengthStartEndLength
11777715563315570977
2781426515599015605465
31432197720100720108377
4220510291229096229386291
5511624114254526254639114
66257027825670425678178
7703442837262685792723043726
844294635207272496272702207
946364770135272871273005135
10477148326227623127629262
1148334980148281534281681148
1249815321341285868286208341
13532254038230166330174482
1454045516113305804305916113
155517944539293061363100643929
TOTAL LENGTH : 9445

Variant 4mRNAGene
Exon StartEndLengthStartEndLength
11777715563315570977
2781426515599015605465
31432197720100720108377
4220510291229096229386291
5511624114254526254639114
66257027825670425678178
77037646227623127629262
8765912148281534281681148
99131253341285868286208341
10125413469329954929964193
11134714288230166330174482
1214291541113305804305916113
131542547039293061363100643929
TOTAL LENGTH : 5470

Variant 2mRNAGene
 ExonStarEndLengthStartEndLength
11777715563315570977
2781426515599015605465
31432197720100720108377
4220510291229096229386291
5511624114254526254639114
66257027825670425678178
77037646227623127629262
8765912148281534281681148
99131253341285868286208341
10125413358230166330174482
1113361448113305804305916113
121449537739293061363100643929
TOTAL LENGTH : 5377

*There is a discrepancy between base pair numbers recorded for the transcript and the gene for this exon.

Pseudogene

None.

Proteins

Note

MAP2 is an approximately 1827 amino acid long protein with an estimated molecular weight of 200 kDa, with the exact molecular weight varying by isoform. Four isoforms have been characterized, but additional ones are thought to exist. The protein undergoes post-translational phosphorylation upon DNA damage. The phosphorylation is hypothesized to be catalyzed by ATM or ATR. In the rat brain, the various isoforms were characterized at different stages of development - isoform MAP2B is found throughout rat brain development, while MAP2A appears towards the end of the second week of post-natal life. MAP2C is found during the early development of the brain, but after maturation is only found in the neural cells of the retina, olfactory bulb and the cerebellum.

Description

MAP2 is a mostly unfolded protein that changes conformation upon binding to its target molecule. A domain near its carboxyl terminus enables MAP2 protein to bind to the microtubules. A 31 amino acid long repeating motif is characteristic of this protein. However, it is found that this motif is not sufficient by itself to bind to microtubules. Two contiguous sequences on either end of this repeating structure on both the amino and carboxyl ends enable the binding of this protein to the microtubules. A proline rich domain on the amino end is thought to be especially crucial in this process. The protein is known to have three tubulin binding domains spanning residues 1160-1691; 1692-1722; 1723-1754. The protein also has a projection domain which extends from residues 377-1505. All isoforms have a conserved C-terminal domain which contain tubulin binding repeats and a conserved N-terminal projection domain. The projection domain varies in size across isoforms, has a net negative charge and exerts a long range repulsive force. This gives a potential mechanism that explains how MAP2 regulates the spacing between microtubules.

Expression

MAP2 plays a major role in dendrite morphogenesis and is normally expressed in neurons. It has also been reported to be ectopically expressed in several cancers including melanoma and breast cancer.

Localisation

MAP2 mRNAs were found in the avian neuronal cell body cytoplasm; however the protein was found localized to the dendrites in mammals (Cristofanilli et al., 2004). The same report shows that avian neuronal MAP2 mRNA lacks a dendritic targeting element in its 3 UTR. Local expression within dendrites is hypothesized to be more suited to regulate need based synthesis. Tubulin, a protein expressed in both axons and dendrites is known to be expressed in the cytoplasm of the cell body showing that location specific expression of proteins is important to the maintenance of polarity of the neural cells.

Function

MAP2 stabilizes microtubule bundling and stiffening through the interactions of several weak binding sites to the microtubules on the protein. The strength of bundling of microtubules is directly correlated to the strength of the binding to MAP2. This enables the microtubules to support outgrowth from the cells. When MAP2 was expressed by transfection in non neuronal cells, it induced the rearrangement of the microtubules into long bundles. These bundles enabled outgrowths from the non neuronal cells. Experiments done with knockout mice show that the role of MAP2 in neuronal morphogenesis may be redundant (Teng et al., 2001). Single knockouts of MAP2 did not show any severe phenotypes but simultaneous knockouts of MAP2 and MAP1B died in the prenatal stage (Teng et al., 2001). There are several reports of functional redundancy amongst the MAP proteins.

Homology

A microtubule associated protein with similar function to MAP2 is known to be expressed in the rat (Rattus norvegicus), chicken (Gallus gallus) and lizard (Anolis carolinensis) with varying levels of sequence homology. In the fruit fly, the tau gene seems to perform a similar function.

Mutations

Note

35 SNPs associated with MAP2 have been identified. The CAGs, which are a set of trinucleotide sequences starting at exon 1 of the MAP2 gene on the 5 UTR region, are conserved in the general population (Kalcheva et al., 1999).

Implicated in

Entity name
Melanoma
Note
It has been found by Soltani et al. that primary melanomas that express the MAP2 gene have a lower rate of metastasis later on than primary melanomas that do not express the MAP2 gene. It has been proposed that MAP2 expression disrupts microtubule formation in cancer cells and interferes with cell cycle progression.
Entity name
Multiple sclerosis lesions
Note
Novel transcript of MAP2 that expresses exon 13 is shown to be up-regulated in multiple sclerosis lesions (Shafit-Zagardo et al., 1998). They proposed that this transcript is involved in remyelination of oligodendrocytes.
Entity name
Alzheimers disease
Note
Abnormal hyperphosphorylation of several tau proteins, MAP1 and MAP2 have been implicated in leading to progressive degeneration and loss of connectivity between neurons.
Entity name
Various diseases
Note
MAP2 expression is altered in response to various illnesses and thus is used as a marker in the diagnosis of many specific illnesses and especially as a marker of neuronal differentiation.

Bibliography

Pubmed IDLast YearTitleAuthors
153286072004Neuronal MAP2 mRNA: species-dependent differential dendritic targeting competence.Cristofanilli M et al
156421082005The MAP2/Tau family of microtubule-associated proteins.Dehmelt L et al
191840682009Mechanisms of tau-induced neurodegeneration.Iqbal K et al
103355521999Survey for CAG repeat polymorphisms in the human MAP-2 gene.Kalcheva N et al
105826151999A novel microtubule-associated protein-2 expressed in oligodendrocytes in multiple sclerosis lesions.Shafit-Zagardo B et al
159201682005Microtubule-associated protein 2, a marker of neuronal differentiation, induces mitotic defects, inhibits growth of melanoma cells, and predicts metastatic potential of cutaneous melanoma.Soltani MH et al
115812862001Synergistic effects of MAP2 and MAP1B knockout in neuronal migration, dendritic outgrowth, and microtubule organization.Teng J et al

Other Information

Locus ID:

NCBI: 4133
MIM: 157130
HGNC: 6839
Ensembl: ENSG00000078018

Variants:

dbSNP: 4133
ClinVar: 4133
TCGA: ENSG00000078018
COSMIC: MAP2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000078018ENST00000199940P11137
ENSG00000078018ENST00000360351P11137
ENSG00000078018ENST00000360351A0A024R407
ENSG00000078018ENST00000361559P11137
ENSG00000078018ENST00000361559A0A024R409
ENSG00000078018ENST00000392193A8MZ31
ENSG00000078018ENST00000392194P11137
ENSG00000078018ENST00000392194A0A024R409
ENSG00000078018ENST00000445941E7EV03
ENSG00000078018ENST00000447185P11137
ENSG00000078018ENST00000452717H7BZB9

Expression (GTEx)

0
50
100
150
200

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
120820792002MAP2 and tau bind longitudinally along the outer ridges of microtubule protofilaments.102
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
154659822004Reduced spinophilin but not microtubule-associated protein 2 expression in the hippocampal formation in schizophrenia and mood disorders: molecular evidence for a pathology of dendritic spines.56
191655272009Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.56
166118222006Tubulin-mediated binding of human immunodeficiency virus-1 Tat to the cytoskeleton causes proteasomal-dependent degradation of microtubule-associated protein 2 and neuronal damage.34
224034092012The protein phosphatase PP2A/Bα binds to the microtubule-associated proteins Tau and MAP2 at a motif also recognized by the kinase Fyn: implications for tauopathies.26
258186302015Loss of Microtubule-Associated Protein 2 Immunoreactivity Linked to Dendritic Spine Loss in Schizophrenia.25
266374292016Multilevel analysis of neuropathogenesis of neurocognitive impairment in HIV.22
198805192010Oncogenic BRAFV600E induces expression of neuronal differentiation marker MAP2 in melanoma cells by promoter demethylation and down-regulation of transcription repressor HES1.19

Citation

Ashika Jayanthy ; Vijayasaradhi Setaluri

MAP2 (microtubule-associated protein 2)

Atlas Genet Cytogenet Oncol Haematol. 2011-08-01

Online version: http://atlasgeneticsoncology.org/gene/44216/map2