FHL2

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Four and a half LIM domains protein 2 also known as FHL-2 is a protein that in humans is encoded by the FHL2 gene.[1] LIM proteins contain a highly conserved double zinc finger motif called the LIM domain.[2]

Function

FHL-2 is thought to have a role in the assembly of extracellular membranes and may function as a link between presenilin-2 and an intracellular signaling pathway.[2]

Family

The Four-and-a-half LIM (FHL)-only protein subfamily is one of the members of the LIM-only protein family. Protein members within the group might be originated from a common ancestor and share a high degree of similarity in their amino acid sequence.[3] These proteins are defined by the presence of the four and a half cysteine-rich LIM homeodomain with the half-domain always located in the N-terminal.[4] The name LIM was derived from the first letter of the transcription factors LIN-11, ISL-1 and MEC-3, from which the domain was originally characterized.[5] No direct interactions between LIM domain and DNA have been reported. Instead, extensive evidence points towards the functional role of FHL2 in supporting protein-protein interactions of LIM-containing proteins and its binding partners.[6][7][8][9] Thus far, five members have been categorized into the FHL subfamily, which are FHL1, FHL2, FHL3, FHL4 and activator of CREM in testis (ACT) in human.[10] FHL1, FHL2 and FHL3 are predominantly expressed in muscle,[11][12] while FHL4 and FHL5 are expressed exclusively in testis.[13]

Gene

FHL2 is the best studied member within the subfamily. The protein is encoded by the fhl2 gene being mapped in the region of human chromosome 2q12-q14.[14] Two alternative promoters, 1a and 1b, as well as 5 transcript variants of fhl2 have been reported.[15]

Tissue distribution

FHL2 exhibits diverse expression patterns in a cell/tissue-specific manner, which has been found in liver, kidney, lung, ovary, pancreas, prostate, stomach, colon, cortex, and in particular, the heart. However, its expression in some immune-related tissues like the spleen, thymus and blood leukocytes has not been documented.[16] Intriguingly, the FHL2 expression and function varies significantly between different types of cancer.[15][17][18][19] Such discrepancies are most likely due to the existence of the wide variety of transcription factors governing FHL2 expression.

Regulation of expression

Different transcription factors that have been reported responsible for the regulation of fhl2 expression include the well-known tumor suppressor protein p53,[15][20] serum response factor (SRF),[21][22] specificity protein 1 (Sp1).[23] the pleiotropic factor IL-1β,[24] MEF-2,[10] and activator protein-1 (AP-1).[25] Apart from being regulated by different transcription factors, FHL2 is itself involved extensively in regulating the expression of other genes. FHL2 exerts its transcriptional regulatory effects by functioning as an adaptor protein interacting indirectly with the targeted genes. In fact, LIM domain is a platform for the formation of multimeric protein complexes.[26] Therefore, FHL2 can contribute to human carcinogenesis by interacting with transcription factors of cancer-related genes and modulates the signaling pathways underlying the expression of these genes. Different types of cancer are associated with FHL2 which act either as the cancer suppressor or inducer, for example in breast cancer, gastrointestinal (GI) cancers, liver cancer and prostate cancer.

Clinical significance

The expression and functions of FHL2 varies greatly depending on the cancer types. It appeared that phenomenon is highly related to the differential mechanistic transcriptional regulations of FHL2 in the various types of cancer. However, the participation of fhl2 mutations and the posttranslational modifications of fhl2 in carcinogenesis cannot be ignored. In fact, functional mutation of fhl2 has been identified in a patient with familial dilated cardiomyopathy (DCM) and is associated with its pathogenesis.[27] This implied that fhl2 mutation may also profoundly affect the diverse cancer progressions. However, records describing the effects of fhl2 mutations on carcinogenesis are scarce.

Phosphorylation of FHL-2 protein has no significant effects on FHL2 functioning both in vitro and in vivo.[28][29] Provided that the existence of posttranscriptional modifications on FHL2 other than phosphorylation is still unclear and FHL2 functions almost exclusively through protein-protein interactions, research works in this direction is still interested. In particular, the mechanisms underpinning the subcellular localization of FHL2 should be focused. FHL2 can traffic freely between nuclear and the different cellular compartments.[10] It also interacts with other proteinaceous binding partners belonging to different functional classes including, but not limited to, transcription factors and signal transducers.[6][12][30][31] Therefore, FHL2 translocation could be important in regulating the different molecular signaling pathways which modify carcinogenesis, for example, nuclear translocation of FHL2 is related to aggressiveness and recurrence of prostate cancer[32] Similar evidence also has been identified in experiment using A7FIL+ cells and NIH 3T3 cell line as the disease model.[16][33][34]

Breast cancer

The FHL2 protein interacts with the breast cancer type 1 susceptibility gene (BRCA1) which enhances the transactivation of BRCA1.[35] In addition, intratumoral FHL2 level was one of the factors determining the worse survival of breast cancer patients[36]

Gastrointestinal cancer

FHL2 is related to gastrointestinal cancers and in particular, colon cancer. Fhl2 demonstrates an oncogenic property in colon cancer which induces the differentiation of some in vitro colon cancer models.[17][37][38] FHL2 is as well crucial to colon cancer cells invasion, migration and adhesion to extracellular matrix. The expression of FHL2 is positively regulated by transforming growth factor beta 1 (TGF-β1) stimulations which induces epithelial-mesenchymal transition (EMT) and endows cancer cells with metastatic properties. The TGF-β1-midiated alternation of FHL2 expression level might therefore trigger colon cell invasion. Besides, the subcellular localization of FHL2 can be modulated by TGF-β1 in sporadic colon cancer which resulted in the polymerization of alpha smooth muscle actin (α-SMA).[39] This process induces the fibroblast to take up a myofibroblast phenotype and contributes to cancer invasion. FHL2 can also induce EMT and cancer cell migration by affecting the structural integrity of membrane-associated E-cadherin-β-catenin complex.[40]

Liver cancer

In the most common form liver cancer, the hepatocellular carcinoma (HCC), FHL2 is always downregulated in the clinical samples.[15] Therefore, fhl2 is exhibiting a tumor-suppressive effect on HCC. Similar to p53, overexpression of FHL2 inhibit the proliferative activity of the HCC Hep3B cell line by decreasing its cyclin D1 expression and increasing P21 and P27 expression supporting the time-dependent cellular repair process.[41] Of note, a database of FHL2-regulated genes in murine liver has recently been established by using microarray and bioinformatics analysis, which provide useful information concerning most of the pathways and new genes related to FHL2.[42]

Prostate cancer

The molecular communication between androgen receptor (AR) and FHL2 is linked to the disease development of prostate cancer such as aggressiveness and biochemical recurrence (i.e., rise in circulatory prostate-specific antigen (PSA) levels after surgical or radiography treatment)[43][44] FHL2 expression is profoundly initiated by androgen through the mediation of serum response factor (SFR) and the RhoA / actin / megakaryocytic acute leukemia (MAL) signaling axis functioning upstream of SRF.[45][46] On the other hand, FHL2 is the coactivator of AR and is able to modulate AR signaling by altering the effect of Aryl hydrocarbon receptor (AhR) imposing AR activity with as yet unknown mechanisms.[47] Calpain cleavage of cytoskeletal protein filamin which is increased in prostate cancer could induce the nuclear translocation of FHL2, and this subsequently increase AR coactivation.[48]

Interactions

FHL2 has been shown to interact with:

References

  1. ↑ Morgan MJ, Madgwick AJ (October 1996). "Slim defines a novel family of LIM-proteins expressed in skeletal muscle". Biochem. Biophys. Res. Commun. 225 (2): 632–8. doi:10.1006/bbrc.1996.1222. PMID 8753811.
  2. ↑ 2.0 2.1 "Entrez Gene: FHL2 four and a half LIM domains 2".
  3. ↑ Fimia GM, De Cesare D, Sassone-Corsi P (Nov 2000). "A family of LIM-only transcriptional coactivators: tissue-specific expression and selective activation of CREB and CREM". Molecular and Cellular Biology. 20 (22): 8613–8622. doi:10.1128/mcb.20.22.8613-8622.2000. PMC 102166. PMID 11046156.
  4. ↑ Kurakula K, Sommer D, Sokolovic M, Moerland PD, Scheij S, van Loenen PB, Koenis DS, Zelcer N, van Tiel CM, de Vries CJ (Jan 2015). "LIM-only protein FHL2 is a positive regulator of liver X receptors in smooth muscle cells involved in lipid homeostasis". Molecular and Cellular Biology. 35 (1): 52–62. doi:10.1128/MCB.00525-14. PMC 4295390. PMID 25332231.
  5. ↑ Way JC, Chalfie M (Jul 1988). "mec-3, a homeobox-containing gene that specifies differentiation of the touch receptor neurons in C. elegans". Cell. 54 (1): 5–16. doi:10.1016/0092-8674(88)90174-2. PMID 2898300.
  6. ↑ 6.0 6.1 Schmeichel KL, Beckerle MC (Oct 1994). "The LIM domain is a modular protein-binding interface". Cell. 79 (2): 211–9. doi:10.1016/0092-8674(94)90191-0. PMID 7954790.
  7. ↑ Breen JJ, Agulnick AD, Westphal H, Dawid IB (Feb 1998). "Interactions between LIM domains and the LIM domain-binding protein Ldb1". The Journal of Biological Chemistry. 273 (8): 4712–7. doi:10.1074/jbc.273.8.4712. PMID 9468533.
  8. ↑ Kadrmas JL, Beckerle MC (Nov 2004). "The LIM domain: from the cytoskeleton to the nucleus". Nature Reviews Molecular Cell Biology. 5 (11): 920–31. doi:10.1038/nrm1499. PMID 15520811.
  9. ↑ Frank D, Kuhn C, Katus HA, Frey N (Jun 2006). "The sarcomeric Z-disc: a nodal point in signalling and disease". Journal of Molecular Medicine. 84 (6): 446–68. doi:10.1007/s00109-005-0033-1. PMID 16416311.
  10. ↑ 10.0 10.1 10.2 Johannessen M, Møller S, Hansen T, Moens U, Van Ghelue M (Feb 2006). "The multifunctional roles of the four-and-a-half-LIM only protein FHL2". Cellular and Molecular Life Sciences. 63 (3): 268–84. doi:10.1007/s00018-005-5438-z. PMID 16389449.
  11. ↑ Samson T, Smyth N, Janetzky S, Wendler O, Müller JM, Schüle R, von der Mark H, von der Mark K, Wixler V (Jul 2004). "The LIM-only proteins FHL2 and FHL3 interact with alpha- and beta-subunits of the muscle alpha7beta1 integrin receptor". The Journal of Biological Chemistry. 279 (27): 28641–52. doi:10.1074/jbc.M312894200. PMID 15117962.
  12. ↑ 12.0 12.1 12.2 Ng EK, Chan KK, Wong CH, Tsui SK, Ngai SM, Lee SM, Kotaka M, Lee CY, Waye MM, Fung KP (2002). "Interaction of the heart-specific LIM domain protein, FHL2, with DNA-binding nuclear protein, hNP220". J. Cell. Biochem. 84 (3): 556–66. doi:10.1002/jcb.10041. PMID 11813260.
  13. ↑ Morgan MJ, Madgwick AJ (Feb 1999). "The fourth member of the FHL family of LIM proteins is expressed exclusively in the testis". Biochemical and Biophysical Research Communications. 255 (2): 251–5. doi:10.1006/bbrc.1999.0180. PMID 10049694.
  14. ↑ Chan KK, Tsui SK, Lee SM, Luk SC, Liew CC, Fung KP, Waye MM, Lee CY (Apr 1998). "Molecular cloning and characterization of FHL2, a novel LIM domain protein preferentially expressed in human heart". Gene. 210 (2): 345–50. doi:10.1016/S0378-1119(97)00644-6. PMID 9573400.
  15. ↑ 15.0 15.1 15.2 15.3 Xu J, Zhou J, Li MS, Ng CF, Ng YK, Lai PB, Tsui SK (2014). "Transcriptional regulation of the tumor suppressor FHL2 by p53 in human kidney and liver cells". PLOS ONE. 9 (8): e99359. doi:10.1371/journal.pone.0099359. PMC 4133229. PMID 25121502.
  16. ↑ 16.0 16.1 Zheng Q, Zhao Y (Sep 2007). "The diverse biofunctions of LIM domain proteins: determined by subcellular localization and protein-protein interaction". Biology of the Cell / Under the Auspices of the European Cell Biology Organization. 99 (9): 489–502. doi:10.1042/BC20060126. PMID 17696879.
  17. ↑ 17.0 17.1 Wu Y, Guo Z, Zhang D, Zhang W, Yan Q, Shi X, Zhang M, Zhao Y, Zhang Y, Jiang B, Cheng T, Bai Y, Wang J (Nov 2013). "A novel colon cancer gene therapy using rAAV‑mediated expression of human shRNA-FHL2". International Journal of Oncology. 43 (5): 1618–26. doi:10.3892/ijo.2013.2090. PMID 24008552.
  18. ↑ Chan KK, Tsui SK, Ngai SM, Lee SM, Kotaka M, Waye MM, Lee CY, Fung KP (Jan 2000). "Protein-protein interaction of FHL2, a LIM domain protein preferentially expressed in human heart, with hCDC47". Journal of Cellular Biochemistry. 76 (3): 499–508. doi:10.1002/(SICI)1097-4644(20000301)76:3<499::AID-JCB16>3.0.CO;2-4. PMID 10649446.
  19. ↑ Tanahashi H, Tabira T (Sep 2000). "Alzheimer's disease-associated presenilin 2 interacts with DRAL, an LIM-domain protein". Human Molecular Genetics. 9 (15): 2281–9. doi:10.1093/oxfordjournals.hmg.a018919. PMID 11001931.
  20. ↑ Tanahashi H, Tabira T (Sep 2000). "Alzheimer's disease-associated presenilin 2 interacts with DRAL, an LIM-domain protein". Human Molecular Genetics. 9 (15): 2281–9. doi:10.1093/oxfordjournals.hmg.a018919. PMID 11001931.
  21. ↑ Heemers HV, Regan KM, Dehm SM, Tindall DJ (Nov 2007). "Androgen induction of the androgen receptor coactivator four and a half LIM domain protein-2: evidence for a role for serum response factor in prostate cancer". Cancer Research. 67 (21): 10592–9. doi:10.1158/0008-5472.CAN-07-1917. PMID 17975004.
  22. ↑ Philippar U, Schratt G, Dieterich C, Müller JM, Galgóczy P, Engel FB, Keating MT, Gertler F, Schüle R, Vingron M, Nordheim A (Dec 2004). "The SRF target gene Fhl2 antagonizes RhoA/MAL-dependent activation of SRF". Molecular Cell. 16 (6): 867–80. doi:10.1016/j.molcel.2004.11.039. PMID 15610731.
  23. ↑ Guo Z, Zhang W, Xia G, Niu L, Zhang Y, Wang X, Zhang Y, Jiang B, Wang J (Sep 2010). "Sp1 upregulates the four and half lim 2 (FHL2) expression in gastrointestinal cancers through transcription regulation". Molecular Carcinogenesis. 49 (9): 826–36. doi:10.1002/mc.20659. PMID 20607723.
  24. ↑ Joos H, Albrecht W, Laufer S, Reichel H, Brenner RE. "IL-1beta regulates FHL2 and other cytoskeleton-related genes in human chondrocytes". Molecular Medicine. 14 (3–4): 150–9. doi:10.2119/2007-00118.Joos. PMC 2213891. PMID 18224250.
  25. ↑ Morlon A, Sassone-Corsi P (Apr 2003). "The LIM-only protein FHL2 is a serum-inducible transcriptional coactivator of AP-1". Proceedings of the National Academy of Sciences of the United States of America. 100 (7): 3977–82. doi:10.1073/pnas.0735923100. PMC 153033. PMID 12644711.
  26. ↑ Bach I (Mar 2000). "The LIM domain: regulation by association". Mechanisms of Development. 91 (1–2): 5–17. doi:10.1016/s0925-4773(99)00314-7. PMID 10704826.
  27. ↑ Arimura T, Hayashi T, Matsumoto Y, Shibata H, Hiroi S, Nakamura T, Inagaki N, Hinohara K, Takahashi M, Manatsu SI, Sasaoka T, Izumi T, Bonne G, Schwartz K, Kimura A (May 2007). "Structural analysis of four and half LIM protein-2 in dilated cardiomyopathy". Biochemical and Biophysical Research Communications. 357 (1): 162–7. doi:10.1016/j.bbrc.2007.03.128. PMID 17416352.
  28. ↑ El Mourabit H, Müller S, Tunggal L, Paulsson M, Aumailley M (Nov 2003). "Characterization of recombinant and natural forms of the human LIM domain-containing protein FHL2". Protein Expression and Purification. 32 (1): 95–103. doi:10.1016/S1046-5928(03)00211-0. PMID 14680945.
  29. ↑ Purcell NH, Darwis D, Bueno OF, Müller JM, Schüle R, Molkentin JD (Feb 2004). "Extracellular signal-regulated kinase 2 interacts with and is negatively regulated by the LIM-only protein FHL2 in cardiomyocytes". Molecular and Cellular Biology. 24 (3): 1081–1095. doi:10.1128/mcb.24.3.1081-1095.2004. PMC 321437. PMID 14729955.
  30. ↑ Wei Y, Renard CA, Labalette C, Wu Y, Lévy L, Neuveut C, Prieur X, Flajolet M, Prigent S, Buendia MA (Feb 2003). "Identification of the LIM protein FHL2 as a coactivator of beta-catenin". The Journal of Biological Chemistry. 278 (7): 5188–94. doi:10.1074/jbc.M207216200. PMID 12466281.
  31. ↑ Lange S, Auerbach D, McLoughlin P, Perriard E, Schäfer BW, Perriard JC, Ehler E (Dec 2002). "Subcellular targeting of metabolic enzymes to titin in heart muscle may be mediated by DRAL/FHL-2". Journal of Cell Science. 115 (Pt 24): 4925–36. doi:10.1242/jcs.00181. PMID 12432079.
  32. ↑ Kahl P, Gullotti L, Heukamp LC, Wolf S, Friedrichs N, Vorreuther R, Solleder G, Bastian PJ, Ellinger J, Metzger E, Schüle R, Buettner R (Dec 2006). "Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence". Cancer Research. 66 (23): 11341–7. doi:10.1158/0008-5472.CAN-06-1570. PMID 17145880.
  33. ↑ Brown JR, Nigh E, Lee RJ, Ye H, Thompson MA, Saudou F, Pestell RG, Greenberg ME (Sep 1998). "Fos family members induce cell cycle entry by activating cyclin D1". Molecular and Cellular Biology. 18 (9): 5609–19. doi:10.1128/mcb.18.9.5609. PMC 109145. PMID 9710644.
  34. ↑ McGrath MJ, Binge LC, Sriratana A, Wang H, Robinson PA, Pook D, Fedele CG, Brown S, Dyson JM, Cottle DL, Cowling BS, Niranjan B, Risbridger GP, Mitchell CA (Aug 2013). "Regulation of the transcriptional coactivator FHL2 licenses activation of the androgen receptor in castrate-resistant prostate cancer". Cancer Research. 73 (16): 5066–79. doi:10.1158/0008-5472.CAN-12-4520. PMID 23801747.
  35. ↑ Yan J, Zhu J, Zhong H, Lu Q, Huang C, Ye Q (Oct 2003). "BRCA1 interacts with FHL2 and enhances FHL2 transactivation function". FEBS Letters. 553 (1–2): 183–9. doi:10.1016/s0014-5793(03)00978-5. PMID 14550570.
  36. ↑ Gabriel B, Fischer DC, Orlowska-Volk M, zur Hausen A, Schüle R, Müller JM, Hasenburg A (Jan 2006). "Expression of the transcriptional coregulator FHL2 in human breast cancer: a clinicopathologic study". Journal of the Society for Gynecologic Investigation. 13 (1): 69–75. doi:10.1016/j.jsgi.2005.10.001. PMID 16378916.
  37. ↑ Amann T, Egle Y, Bosserhoff AK, Hellerbrand C (Jun 2010). "FHL2 suppresses growth and differentiation of the colon cancer cell line HT-29". Oncology Reports. 23 (6): 1669–74. doi:10.3892/or_00000810. PMID 20428824.
  38. ↑ Wang J, Yang Y, Xia HH, Gu Q, Lin MC, Jiang B, Peng Y, Li G, An X, Zhang Y, Zhuang Z, Zhang Z, Kung HF, Wong BC (Mar 2007). "Suppression of FHL2 expression induces cell differentiation and inhibits gastric and colon carcinogenesis". Gastroenterology. 132 (3): 1066–76. doi:10.1053/j.gastro.2006.12.004. PMID 17383428.
  39. ↑ Gullotti L, Czerwitzki J, Kirfel J, Propping P, Rahner N, Steinke V, Kahl P, Engel C, Schüle R, Buettner R, Friedrichs N (Dec 2011). "FHL2 expression in peritumoural fibroblasts correlates with lymphatic metastasis in sporadic but not in HNPCC-associated colon cancer". Laboratory Investigation. 91 (12): 1695–705. doi:10.1038/labinvest.2011.109. PMID 21826055.
  40. ↑ Zhang W, Jiang B, Guo Z, Sardet C, Zou B, Lam CS, Li J, He M, Lan HY, Pang R, Hung IF, Tan VP, Wang J, Wong BC (Jul 2010). "Four-and-a-half LIM protein 2 promotes invasive potential and epithelial-mesenchymal transition in colon cancer". Carcinogenesis. 31 (7): 1220–9. doi:10.1093/carcin/bgq094. PMID 20460358.
  41. ↑ Ng CF, Ng PK, Lui VW, Li J, Chan JY, Fung KP, Ng YK, Lai PB, Tsui SK (May 2011). "FHL2 exhibits anti-proliferative and anti-apoptotic activities in liver cancer cells". Cancer Letters. 304 (2): 97–106. doi:10.1016/j.canlet.2011.02.001. PMID 21377781.
  42. ↑ Ng CF, Xu JY, Li MS, Tsui SK (Apr 2014). "Identification of FHL2-regulated genes in liver by microarray and bioinformatics analysis". Journal of Cellular Biochemistry. 115 (4): 744–53. doi:10.1002/jcb.24714. PMID 24453047.
  43. ↑ Heemers HV, Regan KM, Schmidt LJ, Anderson SK, Ballman KV, Tindall DJ (Apr 2009). "Androgen modulation of coregulator expression in prostate cancer cells". Molecular Endocrinology. 23 (4): 572–83. doi:10.1210/me.2008-0363. PMC 2667711. PMID 19164447.
  44. ↑ Uchio EM, Aslan M, Wells CK, Calderone J, Concato J (Aug 2010). "Impact of biochemical recurrence in prostate cancer among US veterans". Archives of Internal Medicine. 170 (15): 1390–5. doi:10.1001/archinternmed.2010.262. PMID 20696967.
  45. ↑ Heemers HV, Regan KM, Schmidt LJ, Anderson SK, Ballman KV, Tindall DJ (Apr 2009). "Androgen modulation of coregulator expression in prostate cancer cells". Molecular Endocrinology. 23 (4): 572–83. doi:10.1210/me.2008-0363. PMC 2667711. PMID 19164447.
  46. ↑ Schmidt LJ, Duncan K, Yadav N, Regan KM, Verone AR, Lohse CM, Pop EA, Attwood K, Wilding G, Mohler JL, Sebo TJ, Tindall DJ, Heemers HV (May 2012). "RhoA as a mediator of clinically relevant androgen action in prostate cancer cells". Molecular Endocrinology. 26 (5): 716–35. doi:10.1210/me.2011-1130. PMC 3355556. PMID 22456196.
  47. ↑ Kollara A, Brown TJ (Jan 2010). "Four and a half LIM domain 2 alters the impact of aryl hydrocarbon receptor on androgen receptor transcriptional activity". The Journal of Steroid Biochemistry and Molecular Biology. 118 (1–2): 51–8. doi:10.1016/j.jsbmb.2009.09.017. PMID 19815066.
  48. ↑ McGrath MJ, Binge LC, Sriratana A, Wang H, Robinson PA, Pook D, Fedele CG, Brown S, Dyson JM, Cottle DL, Cowling BS, Niranjan B, Risbridger GP, Mitchell CA (Aug 2013). "Regulation of the transcriptional coactivator FHL2 licenses activation of the androgen receptor in castrate-resistant prostate cancer". Cancer Research. 73 (16): 5066–79. doi:10.1158/0008-5472.CAN-12-4520. PMID 23801747.
  49. ↑ Müller JM, Isele U, Metzger E, Rempel A, Moser M, Pscherer A, Breyer T, Holubarsch C, Buettner R, Schüle R (February 2000). "FHL2, a novel tissue-specific coactivator of the androgen receptor". EMBO J. 19 (3): 359–69. doi:10.1093/emboj/19.3.359. PMC 305573. PMID 10654935.
  50. ↑ Yan J, Zhu J, Zhong H, Lu Q, Huang C, Ye Q (October 2003). "BRCA1 interacts with FHL2 and enhances FHL2 transactivation function". FEBS Lett. 553 (1–2): 183–9. doi:10.1016/s0014-5793(03)00978-5. PMID 14550570.
  51. ↑ Yan JH, Ye QN, Zhu JH, Zhong HJ, Zheng HY, Huang CF (December 2003). "[Isolation and characterization of a BRCA1-interacting protein]". Yi Chuan Xue Bao. 30 (12): 1161–6. PMID 14986435.
  52. ↑ Wei Y, Renard CA, Labalette C, Wu Y, Lévy L, Neuveut C, Prieur X, Flajolet M, Prigent S, Buendia MA (February 2003). "Identification of the LIM protein FHL2 as a coactivator of beta-catenin". J. Biol. Chem. 278 (7): 5188–94. doi:10.1074/jbc.M207216200. PMID 12466281.
  53. ↑ 53.0 53.1 53.2 53.3 53.4 Wixler V, Geerts D, Laplantine E, Westhoff D, Smyth N, Aumailley M, Sonnenberg A, Paulsson M (October 2000). "The LIM-only protein DRAL/FHL2 binds to the cytoplasmic domain of several alpha and beta integrin chains and is recruited to adhesion complexes". J. Biol. Chem. 275 (43): 33669–78. doi:10.1074/jbc.M002519200. PMID 10906324.
  54. ↑ 54.0 54.1 Fimia GM, De Cesare D, Sassone-Corsi P (November 2000). "A family of LIM-only transcriptional coactivators: tissue-specific expression and selective activation of CREB and CREM". Mol. Cell. Biol. 20 (22): 8613–22. doi:10.1128/mcb.20.22.8613-8622.2000. PMC 102166. PMID 11046156.
  55. ↑ Li HY, Ng EK, Lee SM, Kotaka M, Tsui SK, Lee CY, Fung KP, Waye MM (2001). "Protein-protein interaction of FHL3 with FHL2 and visualization of their interaction by green fluorescent proteins (GFP) two-fusion fluorescence resonance energy transfer (FRET)". J. Cell. Biochem. 80 (3): 293–303. doi:10.1002/1097-4644(20010301)80:3<293::AID-JCB10>3.0.CO;2-U. PMID 11135358.
  56. ↑ Amaar YG, Thompson GR, Linkhart TA, Chen ST, Baylink DJ, Mohan S (April 2002). "Insulin-like growth factor-binding protein 5 (IGFBP-5) interacts with a four and a half LIM protein 2 (FHL2)". J. Biol. Chem. 277 (14): 12053–60. doi:10.1074/jbc.M110872200. PMID 11821401.
  57. ↑ Samson T, Smyth N, Janetzky S, Wendler O, Müller JM, Schüle R, von der Mark H, von der Mark K, Wixler V (July 2004). "The LIM-only proteins FHL2 and FHL3 interact with alpha- and beta-subunits of the muscle alpha7beta1 integrin receptor". J. Biol. Chem. 279 (27): 28641–52. doi:10.1074/jbc.M312894200. PMID 15117962.
  58. ↑ Purcell NH, Darwis D, Bueno OF, Müller JM, Schüle R, Molkentin JD (February 2004). "Extracellular signal-regulated kinase 2 interacts with and is negatively regulated by the LIM-only protein FHL2 in cardiomyocytes". Mol. Cell. Biol. 24 (3): 1081–95. doi:10.1128/mcb.24.3.1081-1095.2004. PMC 321437. PMID 14729955.
  59. ↑ Tanahashi H, Tabira T (September 2000). "Alzheimer's disease-associated presenilin 2 interacts with DRAL, an LIM-domain protein". Hum. Mol. Genet. 9 (15): 2281–9. doi:10.1093/oxfordjournals.hmg.a018919. PMID 11001931.
  60. ↑ Bai S, Zha J, Zhao H, Ross FP, Teitelbaum SL (November 2008). "Tumor necrosis factor receptor-associated factor 6 is an intranuclear transcriptional coactivator in osteoclasts". J. Biol. Chem. 283 (45): 30861–7. doi:10.1074/jbc.M802525200. PMC 2662164. PMID 18768464.
  61. ↑ Lange S, Auerbach D, McLoughlin P, Perriard E, Schäfer BW, Perriard JC, Ehler E (December 2002). "Subcellular targeting of metabolic enzymes to titin in heart muscle may be mediated by DRAL/FHL-2". J. Cell Sci. 115 (Pt 24): 4925–36. doi:10.1242/jcs.00181. PMID 12432079.
  62. ↑ McLoughlin P, Ehler E, Carlile G, Licht JD, Schäfer BW (October 2002). "The LIM-only protein DRAL/FHL2 interacts with and is a corepressor for the promyelocytic leukemia zinc finger protein". J. Biol. Chem. 277 (40): 37045–53. doi:10.1074/jbc.M203336200. PMID 12145280.

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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