LASP1

Official Full Name

LIM and SH3 protein 1

Organism

Homo sapiens

GeneID

3927

Background

This gene encodes a member of a subfamily of LIM proteins, characterized by a LIM motif and a domain of Src homology region 3, and also a member of the nebulin family of actin-binding proteins. The encoded protein is a cAMP and cGMP dependent signaling protein and binds to the actin cytoskeleton at extensions of the cell membrane. The encoded protein has been linked to metastatic breast cancer, hematopoetic tumors such as B-cell lymphomas, and colorectal cancer. [provided by RefSeq, Oct 2012]

Synonyms

MLN50; Lasp-1;

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Detailed Information

Recent Progress

Since its discovery, LIM and SH3 protein 1 (LASP1) proved to be an extremely versatile protein. Because of its exceptional structure allowing interaction with various binding partners, its common expression in normal tissues, distinct expression patterns, and its ability to transmit signals from the cytoplasm into the nucleus, it has been widely studied. As a result, LASP1 plays key roles in cell structure, physiological processes, and cell signaling. Furthermore, LASP1 overexpression contributes to cancer aggressiveness hinting to a potential value of LASP1 as a cancer biomarker. It has been proved to have a close relationship with esophageal squamous cell carcinoma (ESCC).

LASP1 is an actin-binding protein which is overexpressed in many types of cancers and plays important roles in cancer progression. It was shown by the researchers that LASP1 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) where it promotes invasion and metastasis. Moreover, it was discovered that LASP1 overexpression in PDAC cells was mediated by HIF1α through direct binding to a hypoxia response element in the LASP1 promoter. HIF1α stimulated LASP1 expression in PDAC cells in vitro and mouse tumor xenografts in vivo. Clinically, LASP1 overexpression in PDAC patient specimens was associated significantly with lymph node metastasis and overall survival. Thus LASP1 may be defined as a direct target gene for HIF1α upregulation that is critical for metastatic progression of PDAC.

Lasp1 is also identified as a multidomain protein that may recruit signaling molecules to the actin-based cytoskeleton and is known to concentrate in synaptic sites of hippocampal neurons. In the Korean population, a single-nucleotide polymorphism in the LASP1 gene promoter region was associated with schizophrenia susceptibility. These results suggest that LASP1 might be associated with N-methyl-d-aspartic (NMDA) receptor antagonism and schizophrenia susceptibility and, thus, might be involved in the pathophysiology of schizophrenia.

Moreover, LASP1 was identified as a component of a six gene signature that is strongly predictive for disease progression and relapse in CML (Chronic myeloid leukemia, characterized by a genomic translocation generating a permanently active BCR-ABL oncogene with a complex pattern of atypically tyrosine-phosphorylated proteins) patients. Researchers were able to identify LASP1 as a novel and overexpressed direct substrate of BCR-ABL in CML. Furthermore, it was demonstrated that LASP1 is specifically phosphorylated by BCR-ABL at tyrosine-171 in CML patients, which is abolished by tyrosine kinase inhibitor therapy. Consequently, the BCR-ABL-mediated pathophysiological hyper-phosphorylation of LASP1 in CML disrupts normal regulation of CRKL and LASP1, which likely has implications on downstream BCR-ABL signaling. This means that LASP1 phosphorylation might serve as an additional candidate biomarker for assessment of BCR-ABL activity and provide a first step toward a molecular understanding of LASP1 function in CML.

However, the role of LASP1 in ESCC is not well elucidated. Through various methods, researchers discovered that the expression levels of LASP1 at the mRNA and protein levels were significantly higher in ESCC tissues and ESCC cell lines compared to adjacent tissues. Further analysis showed that LASP1 was localized in the cytoplasm and nuclei of tumor epithelia. Silencing of LASP1 in ECA109 and KYSE510 cell lines significantly inhibited cell proliferation, migration and invasion when compared with the negative control cells in vitro, suggesting that LASP1 may play an important role in the pathogenesis of ESCC and shows promise as a treatment target in ESCC.

References:

Zhao, Tiansuo, et al. "LASP1 is a HIF-1α target gene critical for metastasis of pancreatic cancer." Cancer Research 75.1(2015):111-119.
Joo, J, et al. "Lasp1 is down-regulated in NMDA receptor antagonist-treated mice and implicated in human schizophrenia susceptibility. " Journal of Psychiatric Research 47.1(2013):105-112.
Frietsch, Jochen J., et al. "LASP1 is a novel BCR-ABL substrate and a phosphorylation-dependent binding partner of CRKL in chronic myeloid leukemia." Oncotarget 5.14(2014):5257-5271.
He, B., et al. "Overexpression of LASP1 is associated with proliferation, migration, and invasion in esophageal squamous cell carcinoma. " Oncology Reports 29.3(2013):1115-1123.
Orth, M. F., et al. "An update on the LIM and SH3 domain protein 1 (LASP1): a versatile structural, signaling, and biomarker protein. " Oncotarget 6.1(2015):26-42.

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