LKB1 Somatic Mutations in Sporadic Tumors

Avizienyte, Egle; Loukola, Anu; Roth, Stephan; Hemminki, Akseli; Tarkkanen, Maija; Salovaara, Reijo; Arola, Johanna; Bützow, Ralf; Husgafvel‐Pursiainen, Kirsti; Kokkola, Arto; Järvinen, Heikki; Aaltonen, Lauri A.

doi:10.1016/s0002-9440(10)65314-x

Cited by 116 publications

(91 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Mutational analysis across a range of sporadic tumors has identified loss of function LKB1 mutations most frequently in non-small cell lung carcinomas; between 5 and 17% of cases depending on the population studied (Sanchez-Cespedes et al, 2002;Ji et al, 2007;Koivunen et al, 2008). Somatic inactivating mutations in LKB1 have also been reported in approximately 5% of pancreatic cancers and melanomas, and in single specimens of prostate cancer and cervical cancer (Avizienyte et al, , 1999Bignell et al, 1998;Wang et al, 1998;Guldberg et al, 1999;Rowan et al, 1999;Su et al, 1999;Forster et al, 2000;Ikediobi et al, 2006). Overall, the incidence of LKB1 mutation in sporadic cancers, other than lung cancer, appears low despite the high penetrance of carcinomas associated with PJS.…”

Section: Peutz-jeghers Syndrome and Human Cancer Geneticsmentioning

confidence: 99%

LKB1; linking cell structure and tumor suppression

2008

View full text Add to dashboard Cite

Germ line mutations in the LKB1 tumor suppressor gene are associated with the Peutz-Jeghers polyposis and cancer syndrome. Somatic mutations in Lkb1 are observed in sporadic pulmonary, pancreatic and biliary cancers and melanomas. The LKB1 serine-threonine kinase functionally and biochemically links control of cellular structure and energy utilization through activation of the AMPK family of kinases. Lkb1 regulates cell polarity through downstream kinases including AMPKs, MARKs and BRSKs, and nutrient utilization and cellular metabolism through the AMPK-mTOR pathway. LKB1 has been shown to affect normal chromosomal segregation, TGF-b signaling in the mesenchyme and WNT and p53 activity. Although each of the LKB1-dependent processes and downstream pathways have been individually delineated through work across a range of experimental systems, how they relate to Lkb1's role as a tumor suppressor remains to be fully explored and elucidated. The recent development of mouse cancer models harboring engineered mutations in Lkb1 have offered insights into how LKB1 may be functioning to restrain tumorigenesis and how its role as a master regulator of polarity and metabolism could contribute to its tumor suppressor function.

show abstract

Section: Peutz-jeghers Syndrome and Human Cancer Geneticsmentioning

confidence: 99%

LKB1; linking cell structure and tumor suppression

2008

View full text Add to dashboard Cite

show abstract

“…Germline mutations in LKB1, a tumor suppressor gene mapped to 19p13.3, have been associated with Peutz-Jeghers syndrome (PJS) Jenne et al 1998) whereas somatic mutations in this gene are a rare event in most sporadic tumors Avizienyte et al 1999;Bignell et al 1998;Park et al 1998;Resta et al 1998). Little is known about the role of PTEN and LKB1 genes in (Dürst et al 1987a;Stanley et al 1989;Zheng et al 1994;Hietanen et al 1998).…”

Section: Introductionmentioning

confidence: 99%

Human papillomavirus type 16 in head and neck carcinogenesis

2005

View full text Add to dashboard Cite

“…Most of the mutations in PJS families are point and truncation mutations within the kinase domain of LKB1, suggesting that the kinase activity of LKB1 is critical to its function [4,5]. To date, LKB1 mutations have been identified in only a small percentage of the sporadic tumour types examined [8][9][10][11]. Recently, four point mutations (G163D, D176N, W308C and L67P), which impair the ability of LKB1 to undergo autophosphorylation, have been found in PJS families [12,13].…”

Section: Introductionmentioning

confidence: 99%

LKB1, a novel serine/threonine protein kinase and potential tumour suppressor, is phosphorylated by cAMP-dependent protein kinase (PKA) and prenylated in vivo

Collins

Reoma

Gamm

et al. 2000

Biochemical Journal

163

View full text Add to dashboard Cite

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disease characterized by melanocytic macules, hamartomatous polyps and an increased risk for numerous cancers. The human LKB1 (hLKB1) gene encodes a serine/threonine protein kinase that is deficient in the majority of patients with PJS. The murine LKB1 (mLKB1) cDNA was isolated, sequenced and shown to produce a 2.4-kb transcript encoding a 436 amino acid protein with 90% identity with hLKB1. RNA blot and RNase-protection analysis revealed that mLKB1 mRNA is expressed in all tissues and cell lines examined. The widespread expression of LKB1 transcripts is consistent with the elevated risk of multiple cancer types in PJS patients. The predicted LKB1 protein sequence terminates with a conserved prenylation motif (Cys433-Lys-Gln-Gln436) directly downstream from a consensus cAMP-dependent protein kinase (PKA) phosphorylation site (Arg428-Arg-Leu-Ser431). The expression of enhanced green fluorescent protein (EGFP)-mLKB1 chimaeras demonstrated that LKB1 possesses a functional prenylation motif that is capable of targeting EGFP to cellular membranes. Mutation of Cys433 to an alanine residue, but not phosphorylation by PKA, blocked membrane localization. These findings suggest that PKA does phosphorylate LKB1, although this phosphorylation does not alter the cellular localization of LKB1.

show abstract

LKB1 Somatic Mutations in Sporadic Tumors

Abstract: Peutz-Jeghers syndrome (PJS) is an autosomal dominantly inherited condition characterized by gastrointestinal hamartomatous polyposis and mucocutaneous pigmentation.

Cited by 116 publications

References 17 publications

LKB1; linking cell structure and tumor suppression

LKB1; linking cell structure and tumor suppression

Human papillomavirus type 16 in head and neck carcinogenesis

LKB1, a novel serine/threonine protein kinase and potential tumour suppressor, is phosphorylated by cAMP-dependent protein kinase (PKA) and prenylated in vivo

Contact Info

Product

Resources

About