| Description | Protein 4.1B is a member of the Protein 4.1 superfamily of proteins, which is characterized by the presence of a conserved N-terminal 4.1/ezrin/radixin/moesin (FERM) domain. The full-length protein consists of the following domains (N- to C-termini): U1-FERM-U2-SABD-U3-CTD ("U" = unique domains, SABD = spectrin/actin binding domain, CTD = C-terminal domain).
This protein consists of 1,088 amino acids and has been detected at sizes between 125-145 kDa by Western blot. A truncated variant of Protein 4.1B (named DAL-1) has also been found to be generated by translational initiation at Met110 and termination at Ser542, relative to full-length 4.1B. DAL-1 lacks the 4.1B N-terminal U1 domain and the entire CTD, and also has internal deletions in portions of the U2 and U3 subdomains. DAL-1 is believed to possess the full tumor suppressive capabilities exhibited by full-length Protein 4.1B. |
| Expression | Highly expressed in the brain and neurons, as well as in adipose tissue, adrenal gland, testis, placenta and kidney. Moderate expression in lungs and intestines. Lower expression across many other organs. |
| Localisation | As with other members of the Protein 4.1 superfamily, Protein 4.1B likely functions to link cellular receptors with the cytoskeleton, and thus localizes to the plasma membrane. By immunofluorescence, 4.1B has been reported to display a "honeycomb" pattern, with enrichment at points of cell-cell contact. 4.1B has also been localized to the cytoplasm and, at least in one report, to the nucleus. |
| Function | The tumor suppressive function of 4.1B has been reported in several studies, both in vitro and in vivo. Overexpression of 4.1B can suppress growth and, in some cases, induce apoptosis in human breast cancer, non-small cell lung cancer and meningioma cells. Although the mechanism by which 4.1B induces apoptosis remains unclear, one report has observed that overexpression of 4.1B increases caspase-8 activity in MCF-7 cells, and that inhibitors of caspase-8 can block 4.1B-mediated apoptosis. Others have reported that overexpression of 4.1B induces Rac1-dependent JNK signaling, which leads to growth suppression of meningioma cells. Truncation studies have also suggested that the U2 region of 4.1B contains the minimal growth suppressive domain when tethered to the membrane by FERM domain-mediated protein-protein interactions. Finally, downregulation of 4.1B by shRNAs has been reported to increase metastatic capability in human prostate cancer cells. However, the growth inhibitory effects of 4.1B are not general and may be cell-type-specific. For instance, overexpression of 4.1B inhibits the growth of some subclones of MCF-7 breast cancer cells, but not others, and 4.1B has been reported not to affect the growth of schwannomas.
4.1B knock-out animals are largely normal and fertile, and do not display any detectable predisposition to spontaneous tumor formation above background levels. However, in the TRAMP tumorigenesis model of prostate cancer, 4.1B null mice have been reported to display increased susceptibility for developing primary tumors and metastases. The only non-tumor phenotype observed in mutant animals is that mammary glands from 4.1B-/- female mice displayed a 60% increase in Ki67-positive epithelial cells during pregnancy, but not during the lactating or involution stages. The precise function of 4.1B remains unclear. |
| Homology | The FERM domain of Protein 4.1B is 73% homologous with the FERM domain of Protein 4.1R, the founding member of the Protein 4.1 superfamily of proteins. 4.1B is most similar to other members of the Protein 4.1 sub-group (e.g. 4.1R, 4.1G, 4.1N), which is one branch of the Protein 4.1 superfamily. |
| A novel member of the NF2/ERM/4.1 superfamily with growth suppressing properties in lung cancer. |
| Tran YK., Bogler O, Gorse KM, Wieland I, Green MR, Newsham IF. |
| Cancer Res. 1999 Jan 1;59(1):35-43. |
| PMID 9892180 |
| |
| Loss of DAL-1, a protein 4.1-related tumor suppressor, is an important early event in the pathogenesis of meningiomas. |
| Gutmann DH, Donahoe J, Perry A, Lemke N, Gorse K, Kittiniyom K, Rempel SA, Gutierrez JA, Newsham IF. |
| Hum Mol Genet. 2000 Jun 12;9(10):1495-500. |
| PMID 10888600 |
| |
| The protein 4.1 tumor suppressor, DAL-1, impairs cell motility, but regulates proliferation in a cell-type-specific fashion. |
| Gutmann DH, Hirbe AC, Huang ZY, Haipek CA. |
| Neurobiol Dis. 2001 Apr;8(2):266-78. |
| PMID 11300722 |
| |
| Allelic loss on chromosome band 18p11.3 occurs early and reveals heterogeneity in breast cancer progression. |
| Kittiniyom K, Gorse KM, Dalbegue F, Lichy JH, Taubenberger JK, Newsham IF. |
| Breast Cancer Res. 2001;3(3):192-8. Epub 2001 Feb 12. |
| PMID 11305954 |
| |
| ERM proteins and merlin: integrators at the cell cortex. |
| Bretscher A, Edwards K, Fehon RG. |
| Nat Rev Mol Cell Biol. 2002 Aug;3(8):586-99. |
| PMID 12154370 |
| |
| Suppression of growth and increased cellular attachment after expression of DAL-1 in MCF-7 breast cancer cells. |
| Charboneau AL, Singh V, Yu T, Newsham IF. |
| Int J Cancer. 2002 Jul 10;100(2):181-8. |
| PMID 12115567 |
| |
| Protein 4.1 tumor suppressors: getting a FERM grip on growth regulation. |
| Sun CX, Robb VA, Gutmann DH. |
| J Cell Sci. 2002 Nov 1;115(Pt 21):3991-4000. |
| PMID 12356905 |
| |
| Protein 4.1B in mouse islets of Langerhans and beta-cell tumorigenesis. |
| Terada N, Ohno N, Yamakawa H, Baba T, Fujii Y, Christofori G, Ohara O, Ohno S. |
| Histochem Cell Biol. 2003 Oct;120(4):277-83. Epub 2003 Sep 9. |
| PMID 14574582 |
| |
| Immunolocalization of protein 4.1B/DAL-1 during neoplastic transformation of mouse and human intestinal epithelium. |
| Ohno N, Terada N, Murata S, Yamakawa H, Newsham IF, Katoh R, Ohara O, Ohno S. |
| Histochem Cell Biol. 2004 Dec;122(6):579-86. Epub 2004 Oct 29. |
| PMID 15517334 |
| |
| ONCOMINE: a cancer microarray database and integrated data-mining platform. |
| Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A, Chinnaiyan AM. |
| Neoplasia. 2004 Jan-Feb;6(1):1-6. |
| PMID 15068665 |
| |
| An interaction between alpha(v)beta(8) integrin and Band 4.1B via a highly conserved region of the Band 4.1 C-terminal domain. |
| McCarty JH, Cook AA, Hynes RO. |
| Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13479-83. Epub 2005 Sep 12. |
| PMID 16157875 |
| |
| Membrane localization of the U2 domain of protein 4.1B is necessary and sufficient for meningioma growth suppression. |
| Robb VA, Gerber MA, Hart-Mahon EK, Gutmann DH. |
| Oncogene. 2005 Mar 10;24(11):1946-57. |
| PMID 15688033 |
| |
| Loss of the putative tumor suppressor Band 4.1B/Dal1 gene is dispensible for normal development and does not predispose to cancer. |
| Yi C, McCarty JH, Troutman SA, Eckman MS, Bronson RT, Kissil JL. |
| Mol Cell Biol. 2005 Nov;25(22):10052-9. |
| PMID 16260618 |
| |
| Protein 4.1B/differentially expressed in adenocarcinoma of the lung-1 functions as a growth suppressor in meningioma cells by activating Rac1-dependent c-Jun-NH2-kinase signaling. |
| Gerber MA, Bahr SM, Gutmann DH. |
| Cancer Res. 2006 May 15;66(10):5295-303. |
| PMID 16707455 |
| |
| The tumor suppressor DAL-1/4.1B and protein methylation cooperate in inducing apoptosis in MCF-7 breast cancer cells. |
| Jiang W, Newsham IF. |
| Mol Cancer. 2006 Jan 18;5:4. |
| PMID 16420693 |
| |
| Protein 4.1B suppresses prostate cancer progression and metastasis. |
| Wong SY, Haack H, Kissil JL, Barry M, Bronson RT, Shen S, Whittaker CA, Crowley D, Hynes RO. |
| Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12784-9. Epub 2007 Jul 18. |
| PMID 17640904 |
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