Anti-human CCM1/Krit1; Cerebral cavernous malformations1 protein; Krev interaction trapped protein 1

For Research Use Only. Not for use in diagnostic procedures.

Chromosome: 7; NC_000007.14 (92198969..92246128, complement). Location: 7q21.2

Polyclonal

Rabbit IgG

Rabbit

Protein A purified

Lyophilized

The lyophilized antibody is stable at room temperature for up to 1 month. The reconstituted antibody is stable for at least two weeks at 2-8 degree C. Frozen aliquots are stable for at least 6 months when stored at -20 degree C. Avoid repeated freeze-thaw cycles!

Manufactured in an ISO 9001:2008 Certified Laboratory.

Small volumes of anti-CCM-1 antibody vial(s) may occasionally become entrapped in the seal of the product vial during shipment and storage. If necessary, briefly centrifuge the vial on a tabletop centrifuge to dislodge any liquid in the container`s cap. Certain products may require to ship with dry ice and additional dry ice fee may apply.

Cerebral cavernous malformations (CCM) are frequent vascular abnormalities caused by mutations in one of the CCM genes. CCM-1 (also known as KRIT1) stabilizes endothelial junctions and is essential for vascular morphogenesis in mouse embryos. However, cellular functions of CCM-1 during the early steps of the CCM pathogenesis remain unknown. It was shown that CCM-1 represents an antiangiogenic protein to keep the human endothelium quiescent. CCM-1 inhibits endothelial proliferation, apoptosis, migration, lumen formation, and sprouting angiogenesis in primary human endothelial cells. CCM-1 strongly induces DLL4-NOTCH signaling, which promotes AKT phosphorylation but reduces phosphorylation of the mitogen-activated protein kinase ERK. Consistently, blocking of NOTCH activity alleviates CCM-1 effects. ERK phosphorylation is increased in human CCM lesions. Transplantation of CCM-1-silenced human endothelial cells into SCID mice recapitulates hallmarks of the CCM pathology and serves as a unique CCM model system.

Western Blot (WB), Immunofluorescence (IF)

Western Blot: Use 1-5 ug/ml IF/IHC Use 1:200

84,348 Da

KRIT1, ankyrin repeat containing

krev interaction trapped protein 1; krev interaction trapped 1; ankyrin repeat-containing protein Krit1; cerebral cavernous malformations 1 protein

Krev interaction trapped protein 1

CCM1; Krev interaction trapped 1??[Similar Products]

KRIT1_HUMAN

This gene encodes a protein containing four ankyrin repeats, a band 4.1/ezrin/radixin/moesin (FERM) domain, and multiple NPXY sequences. The encoded protein is localized in the nucleus and cytoplasm. It binds to integrin cytoplasmic domain-associated protein-1 alpha (ICAP1alpha), and plays a critical role in beta1-integrin-mediated cell proliferation. It associates with junction proteins and RAS-related protein 1A (Rap1A), which requires the encoded protein for maintaining the integrity of endothelial junctions. It is also a microtubule-associated protein and may play a role in microtubule targeting. Mutations in this gene result in cerebral cavernous malformations. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2009]

Function: Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity

By similarity. Negative regulator of angiogenesis. Inhibits endothelial proliferation, apoptosis, migration, lumen formation and sprouting angiogenesis in primary endothelial cells. Promotes AKT phosphorylation in a NOTCH-dependent and independent manner, and inhibits ERK1/2 phosphorylation indirectly through activation of the DELTA-NOTCH cascade. Acts in concert with CDH5 to establish and maintain correct endothelial cell polarity and vascular lumen and these effects are mediated by recruitment and activation of the Par polarity complex and RAP1B. Required for the localization of phosphorylated PRKCZ, PARD3, TIAM1 and RAP1B to the cell junction, and cell junction stabilization. Plays a role in integrin signaling via its interaction with ITGB1BP1; this prevents the interaction between ITGB1 and ITGB1BP1. Microtubule-associated protein that binds to phosphatidylinositol 4,5-bisphosphate (PIP2)-containing membranes in a GTP-bound RAP1-dependent manner. Plays an important role in the maintenance of the intracellular reactive oxygen species (ROS) homeostasis to prevent oxidative cellular damage. Regulates the homeostasis of intracellular ROS through an antioxidant pathway involving FOXO1 and SOD2. Facilitates the down-regulation of cyclin-D1 (CCND1) levels required for cell transition from proliferative growth to quiescence by preventing the accumulation of intracellular ROS through the modulation of FOXO1 and SOD2 levels. Ref.11 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.20

Subunit structure: Interacts with CDH5

By similarity. Found in a complex, at least composed of ITGB1BP1, KRIT1 and RAP1A. Interacts (via C-terminus FERM domain) with RAP1A (active GTP-bound form preferentially); the interaction does not induce the opening conformation of KRIT1. Interacts (via FERM domain) with RAP1B. Interacts (via N-terminus NPXY motif) with ITGB1BP1; the interaction induces the opening conformation of KRIT1 and competes with ITGB1 for ITGB1BP1 interaction. Interacts with HEG1 and CCM2; greatly facilitates CCM2-binding to HEG1. Associates (via N-terminus and C-terminus regions) with microtubules; the interaction is inhibited in presence of ITGB1BP1 and active GTP-bound RAP1A. Ref.1 Ref.11 Ref.12 Ref.13 Ref.14 Ref.17 Ref.18 Ref.19 Ref.20

Subcellular location: Cytoplasm ? cytoskeleton. Cell membrane; Peripheral membrane protein. Cell junction. Note: KRIT1 and CDH5 reciprocally regulate their localization to endothelial cell-cell junctions. Association with RAP1 relocalizes KRIT1 from microtubules to cell junction membranes. Translocates from the cytoplasm along microtubules to the cell membrane in a ITGB1BP1-dependent manner. Ref.13 Ref.14 Ref.17 Ref.19

Tissue specificity: Low levels in brain. Very weak expression found in heart and muscle. Ref.1

Domain: The FERM domain mediates binding to RAP1A and RAP1B and is necessary for binding to phosphatidylinositol 4,5-bisphosphate (PIP2). Ref.20The N-terminal domain has structural similarity to the nudix hydrolase domain, despite the absence of a nudix box and low sequence similarity with nudix hydrolase domains. The N-terminus and the C-terminus part associate together via the NPAY binding motif and adopt a lose conformation that is disrupted by ITGB1BP1, but not by RAP1A. Ref.20

Involvement in disease: Cerebral cavernous malformations 1 (CCM1) [MIM:116860]: A congenital vascular anomaly of the central nervous system that can result in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits. The lesions are characterized by grossly enlarged blood vessels consisting of a single layer of endothelium and without any intervening neural tissue, ranging in diameter from a few millimeters to several centimeters.Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.4

Sequence similarities: Contains 4 ANK repeats.Contains 1 FERM domain.

1. Verlaan DJ et al, Neurology 26 (2002) 2. Revencu N and Vikkula M, J Med Genet 43 (2006) 3. Yadla et al, S, Neurosurg Focus 29 (2010) 4. Marchuk et al, Hum Mol Genet 12 Spec No 1 (2003) 5. Liu et al, J Vasc Res 48 (2011)

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