MYH11
Myosin-11 is a protein that in humans is encoded by the MYH11 gene.

# Function
Gene ID: 4629 MYH11 myosin heavy chain 11, "The protein encoded by this gene is a smooth muscle myosin belonging to the myosin heavy chain family. The gene product is a subunit of a hexameric protein that consists of two heavy chain subunits and two pairs of non-identical light chain subunits. It functions as a major contractile protein, converting chemical energy into mechanical energy through the hydrolysis of ATP. The gene encoding a human ortholog of rat NUDE1 is transcribed from the reverse strand of this gene, and its 3' end overlaps with that of the latter. The pericentric inversion of chromosome 16  produces a chimeric transcript that encodes a protein consisting of the first 165 residues from the N terminus of core-binding factor beta in a fusion with the C-terminal portion of the smooth muscle myosin heavy chain. This chromosomal rearrangement is associated with acute myeloid leukemia of the M4Eo subtype. Alternative splicing generates isoforms that are differentially expressed, with ratios changing during muscle cell maturation. Alternatively spliced transcript variants encoding different isoforms have been identified."

# Transcriptions
CArG boxes are present in the promoters of smooth muscle cell (SMC) genes.
"CArG box  DNA  sequences present within the promoters of SMC genes play a pivotal role in controlling their transcription".
"Serum response factor (SRF) controls SMC gene transcription via binding to CArG box DNA sequences found within genes that exhibit SMC-restricted expression."
"SMC genes examined in this study display SMC-specific histone modifications at the 5-CArG boxes."
"The SRF-CArG association is required for transcriptional activation of SMC genes  the SMC genes examined in this study display SMC-specific histone modifications at the 5-CArG boxes.  enrichment of H4 and H3 acetylation  were relatively low from positions 2,800 to 1,600 in the 5 region. However, at position 1,600 to 1,200, there was a sharp rise in these modifications, which was increased even further at +400 in the coding region. We observed similar patterns for H3K4dMe and H3 Lys79 di-methylation . SRF, TFIID, and RNA polymerase II displayed enrichments that were consistent with the positions of the CArG boxes, TATA box, and coding region, respectively".
The CArG boxes occur between -400 and -200 nts, between the Enhancer boxes and the TCE element.
The consensus sequence of CC(A/T)6GG is confirmed.
"MADS-box proteins bind to a consensus sequence, the CArG box, that has the core motif CC(A/T)6GG (15)."
"Of the  FLC binding sites, 69% contained at least one CArG-box motif with the core consensus sequence CCAAAAAT(G/A)G and an AAA extension at the 3 end ."
Three "other MADS-box flowering-time regulators, SOC1, SVP, and AGAMOUS-LIKE 24 (AGL24), bind to two different CArG-box motifs at 502 bp (CTAAATATGG) and 287 bp (CAATAATTGG) upstream of the translation start in the SEP3 gene (24), consistent with different specificities for the different MADS-box proteins." These together with the core motif CC(A/T)6GG (15) suggest a more general CArG-box motif of (C(C/A/T)(A/T)6(A/G)G).
"Exposure of human HL-525 cells to x-rays was associated with increases in EGRI mRNA levels. Nuclear run-on assays showed that this effect is related at least in part to activation of EGRI gene transcription. Sequences responsive to ionizing radiation-induced signals were determined by deletion analysis of the EGRI promoter. The results demonstrate that x-ray inducibility of the EGRI gene is conferred by a region containing six serum response or CC(A+T-rich)6GG (CArG) motifs. Further analysis confirmed that the region encompassing the three distal or upstream CArG elements is functional in the x-ray response. Moreover, this region conferred x-ray inducibility to a minimal thymidine kinase gene promoter. Taken together, these results indicate that ionizing radiation induces EGRI transcription through CArG elements."
"Positively acting, rate-limiting regulatory factors that influence tissue-specific expression of the human cardiac -actin gene in a mouse muscle cell line are shown by in vivo competition and gel mobility-shift assays to bind to upstream regions of its promoter but to neither vector DNA nor a -globin promoter. Although the two binding regions are distinctly separated, each corresponds to a cis region required for muscle-specific transcriptional stimulation, and each contains a core CC(A+T-rich)6GG sequence (designated CArG box), which is found in the promoter regions of several muscle-associated genes. Each site has an apparently different binding affinity for trans-acting factors, which may explain the different transcriptional stimulation activities of the two cis regions.  two CArG box regions are responsible for muscle-specific transcriptional activity of the cardiac -actin gene through a mechanism that involves their binding of a positive trans-acting factor in muscle cells."
"SRF binds to an A/T-rich sequence (CCWWWWWWGG) that has been designated as the CArG box.1012 CArG boxes were originally identified in transcriptional regulatory elements controlling expression of a set of growth- or serum-responsive genes including c-fos and egr-1.13,14 Subsequently, CArG boxes were identified in transcriptional regulatory elements controlling expression of a subset of genes encoding myogenic contractile and cytoskeletal proteins including -cardiac actin, smooth muscle (SM)--actin, -skeletal actin, and SM22.1519"
"Functionally important CArG boxes have been identified in transcriptional regulatory elements controlling expression of sets of myogenic contractile and cytoskeletal proteins (reviewed elsewhere8,25). Of note, in cardiac and skeletal muscle cells, functionally important CArG boxes have been identified in transcriptional regulatory element controlling a relatively limited subset of myofibrillar proteins.26"
"In the nucleus, MRTFs physically associate with SRF, facilitating the binding of SRF to single or dual CArG boxes, activating transcription of genes encoding cytoskeletal and myogenic proteins .39,40,53,55,56"
"The binding of SRF to SMC CArG boxes is associated with specific alterations in chromatin structure including the methylation and acetylation of histones.76,79"
"Both PDGF-BB and KLF-4 inhibit SRF binding to CArG boxes downregulating transcription of SMC contractile genes.92"

# Variants
NP_002465.1 myosin-11 isoform SM1A: "This variant (SM1A) lacks two segments in the coding region, compared to variant SM2B. The encoded isoform (SM1A) is shorter and varies in the carboxyl terminus, compared to isoform SM2B." Conserved Domains (8) summary
- cd14921 (Location:99  771): MYSc_Myh11; class II myosin heavy chain 11, motor domain,
- pfam01576 (Location:848  1928): Myosin_tail_1; Myosin tail,
- pfam02736 (Location:33  71): Myosin_N; Myosin N-terminal SH3-like domain.
NP_074035.1 myosin-11 isoform SM2A: "This variant (SM2A) lacks an in-frame segment of the coding region, compared to variant SM2B. It encodes a shorter isoform (SM2A), that is missing an internal segment compared to isoform SM2B." Conserved Domains (8) summary
- cd14921 (Location:99  771): MYSc_class_II; class II myosins, motor domain,
- pfam00063 (Location:87  771): Myosin_head; Myosin head (motor domain),
- pfam01576 (Location:848  1928): Myosin_tail_1; Myosin tail,
- pfam02736 (Location:34  71): Myosin_N; Myosin N-terminal SH3-like domain,
- pfam09798 (Location:1819  1935): LCD1; DNA damage checkpoint protein,
- pfam16046 (Location:990  1082): FAM76; FAM76 protein,
- cl23717 (Location:1066  1124): "crotonase-like Superfamily: Crotonase/Enoyl-Coenzyme A (CoA) hydratase superfamily. This superfamily contains a diverse set of enzymes including enoyl-CoA hydratase, napthoate synthase, methylmalonyl-CoA decarboxylase, 3-hydoxybutyryl-CoA dehydratase, and dienoyl-CoA isomerase. Many of these play important roles in fatty acid metabolism. In addition to a conserved structural core and the formation of trimers (or dimers of trimers), a common feature in this superfamily is the stabilization of an enolate anion intermediate derived from an acyl-CoA substrate. This is accomplished by two conserved backbone NH groups in active sites that form an oxyanion hole."
- cl24005 (Location:1780  1867): DUF2570; Protein of unknown function (DUF2570).
NP_001035202.1 myosin-11 isoform SM2B: "This variant (SM2B) represents the longer transcript. It encodes the isoform SM2B." Conserved Domains (8) summary
- cd01377 (Location:99  778): MYSc_class_II; class II myosins, motor domain,
- pfam00063 (Location:87  778): Myosin_head; Myosin head (motor domain),
- pfam01576 (Location:855  1935): Myosin_tail_1; Myosin tail,
- pfam02736 (Location:34  71): Myosin_N; Myosin N-terminal SH3-like domain,
- pfam09798 (Location:1826  1942): LCD1; DNA damage checkpoint protein,
- pfam16046 (Location:997  1089): FAM76; FAM76 protein,
- cl23717 (Location:1073  1131): "crotonase-like Superfamily: Crotonase/Enoyl-Coenzyme A (CoA) hydratase superfamily. This superfamily contains a diverse set of enzymes including enoyl-CoA hydratase, napthoate synthase, methylmalonyl-CoA decarboxylase, 3-hydoxybutyryl-CoA dehydratase, and dienoyl-CoA isomerase. Many of these play important roles in fatty acid metabolism. In addition to a conserved structural core and the formation of trimers (or dimers of trimers), a common feature in this superfamily is the stabilization of an enolate anion intermediate derived from an acyl-CoA substrate. This is accomplished by two conserved backbone NH groups in active sites that form an oxyanion hole.",
- cl24005 (Location:1787  1874): DUF2570; Protein of unknown function (DUF2570).
NP_001035203.1 myosin-11 isoform SM1B: "Transcript Variant: This variant (SM1B) lacks a segment in the coding region, which leads to a frameshift, compared to variant SM2B. The encoded isoform (SM1B) is longer and varies in the carboxyl terminus, compared to isoform SM2B." Conserved Domains (8) summary
- cl14654 (Location:1027  1299): V_Alix_like; Protein-interacting V-domain of mammalian Alix and related domains,
- cd01377 (Location:99  778): MYSc_class_II; class II myosins, motor domain,
- pfam00063 (Location:87  778): Myosin_head; Myosin head (motor domain),
- pfam01576 (Location:855  1935): Myosin_tail_1; Myosin tail,
- pfam02736 (Location:34  71): Myosin_N; Myosin N-terminal SH3-like domain,
- pfam16046 (Location:997  1089): FAM76; FAM76 protein,
- cl23717 (Location:1073  1131): "crotonase-like Superfamily: Crotonase/Enoyl-Coenzyme A (CoA) hydratase superfamily. This superfamily contains a diverse set of enzymes including enoyl-CoA hydratase, napthoate synthase, methylmalonyl-CoA decarboxylase, 3-hydoxybutyryl-CoA dehydratase, and dienoyl-CoA isomerase. Many of these play important roles in fatty acid metabolism. In addition to a conserved structural core and the formation of trimers (or dimers of trimers), a common feature in this superfamily is the stabilization of an enolate anion intermediate derived from an acyl-CoA substrate. This is accomplished by two conserved backbone NH groups in active sites that form an oxyanion hole."
- cl24005 (Location:1787  1874): DUF2570; Protein of unknown function (DUF2570).
XP_016878739.1 myosin-11 isoform X1 Conserved Domains (8) summary
- cd01377 (Location:99  778): MYSc_class_II; class II myosins, motor domain,
- pfam00063 (Location:87  778): Myosin_head; Myosin head (motor domain),
- pfam01576 (Location:855  1935): Myosin_tail_1; Myosin tail,
- pfam02736 (Location:34  71): Myosin_N; Myosin N-terminal SH3-like domain,
- pfam09798 (Location:1826  1942): LCD1; DNA damage checkpoint protein,
- pfam16046 (Location:997  1089): FAM76; FAM76 protein,
- cl23717 (Location:1073  1131): "crotonase-like Superfamily: Crotonase/Enoyl-Coenzyme A (CoA) hydratase superfamily. This superfamily contains a diverse set of enzymes including enoyl-CoA hydratase, napthoate synthase, methylmalonyl-CoA decarboxylase, 3-hydoxybutyryl-CoA dehydratase, and dienoyl-CoA isomerase. Many of these play important roles in fatty acid metabolism. In addition to a conserved structural core and the formation of trimers (or dimers of trimers), a common feature in this superfamily is the stabilization of an enolate anion intermediate derived from an acyl-CoA substrate. This is accomplished by two conserved backbone NH groups in active sites that form an oxyanion hole."
- cl24005 (Location:1787  1874): DUF2570; Protein of unknown function (DUF2570).
XP_011520804.1 myosin-11 isoform X2 Conserved Domains (8) summary
- cd14921 (Location:99  771): MYSc_class_II; class II myosin heavy chain 11, motor domain,
- pfam00063 (Location:87  771): Myosin_head; Myosin head (motor domain),
- pfam01576 (Location:848  1928): Myosin_tail_1; Myosin tail,
- pfam02736 (Location:34  71): Myosin_N; Myosin N-terminal SH3-like domain,
- pfam09798 (Location:1826  1942): LCD1; DNA damage checkpoint protein,
- pfam16046 (Location:990  1082): FAM76; FAM76 protein,
- cl23717 (Location:1066  1124): "crotonase-like Superfamily: Crotonase/Enoyl-Coenzyme A (CoA) hydratase superfamily. This superfamily contains a diverse set of enzymes including enoyl-CoA hydratase, napthoate synthase, methylmalonyl-CoA decarboxylase, 3-hydoxybutyryl-CoA dehydratase, and dienoyl-CoA isomerase. Many of these play important roles in fatty acid metabolism. In addition to a conserved structural core and the formation of trimers (or dimers of trimers), a common feature in this superfamily is the stabilization of an enolate anion intermediate derived from an acyl-CoA substrate. This is accomplished by two conserved backbone NH groups in active sites that form an oxyanion hole."
- cl24005 (Location:1780  1867): DUF2570; Protein of unknown function (DUF2570).

# Clinical significance
Thoracic aortic aneurysms leading to acute aortic dissections (TAAD) can be inherited in isolation or in association with genetic syndromes, such as Marfan syndrome and Loeys-Dietz syndrome. When TAAD occurs in the absence of syndromic features, it is inherited in an autosomal dominant manner with decreased penetrance and variable expression, the disease is referred to as familial TAAD.  Familial TAAD exhibits significant clinical and genetic heterogeneity.  Mutations in MYH11 have been described in individuals with TAAD with patent ductus arteriosus (PDA).  Of individuals with TAAD, approximately 4% have mutations in TGFBR2, and approximately 1-2% have mutations in either TGFBR1 or MYH11.  In addition, FBN1 mutations have also been reported in individuals with TAAD.  Mutations within the SMAD3 gene have recently been reported in patients with a syndromic form of aortic aneurysms and dissections with early onset osteoarthritis.  SMAD3 mutations are thought to account for approximately 2% of familial TAAD.  Additionally, mutations in the ACTA2 gene are thought to account for approximately 10-14% of familial TAAD.

# Acute myeloid leukemia
The gene encoding a human ortholog of rat NUDE1 is transcribed from the reverse strand of this gene, and its 3' end overlaps with that of the latter. The pericentric inversion of chromosome 16  produces a chimeric transcript that encodes a protein consisting of the first 165 residues from the N-terminus of core-binding factor beta in a fusion with the C-terminal portion of the smooth muscle myosin heavy chain. This chromosomal rearrangement is associated with acute myeloid leukemia of the M4Eo subtype.

# Intestinal cancer
MYH11 mutations appear to contribute to human intestinal cancer.