LAPTM4B

Official Full Name

lysosomal protein transmembrane 4 beta

Organism

Homo sapiens

GeneID

55353

Background

Enables ceramide binding activity; enzyme binding activity; and phosphatidylinositol bisphosphate binding activity. Involved in several processes, including endosome transport via multivesicular body sorting pathway; negative regulation of macromolecule metabolic process; and regulation of lysosomal membrane permeability. Located in several cellular components, including endosome; lysosomal membrane; and plasma membrane. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

LC27; LAPTM4beta;

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Detailed Information

Recent Progress

Mammalian target of rapamycin 1 (mTORC1), a master regulator of cellular growth, is activated downstream of growth factors, energy signalling and intracellular essential amino acids (EAAs). mTORC1 activation occurs at the lysosomal membrane, and involves V-ATPase stimulation by intra-lysosomal EAA, leading to activation of the Ragulator, RagA/B-GTP and mTORC1 via Rheb-GTP. Researchers identified the lysosomal protein LAPTM4b as a binding partner for the Leu transporter. It was shown that LAPTM4b recruits LAT1-4F2hc to lysosomes, leading to uptake of Leu into lysosomes, and is required for mTORC1 activation via V-ATPase following EAA or Leu stimulation. These results demonstrated a functional Leu transporter at the lysosome, and help explain the inside-out lysosomal activation of mTORC1 by Leu (Fig.1).

Fig. 1. LAPTM4b recruits the Leu transporter to lysosomes. (Rotin et al, 2015)

In one study, researchers investigated the LAPTM4B-35 expression in prostate cancer (PCa) and its potential relevance to clinic-pathological variables and prognosis. Immunohistochemistry was used and 180 PCa tissues along with 180 normal benign prostatic hyperplasia (BPH) specimens were examined. The results showed that LAPTM4B-35 expression was significantly elevated in PCa. High LAPTM4B-35 staining was seen in many of all the cases with PCa. The overexpression of LAPTM4B-35 was significantly associated with the lymph node metastasis, seminal vesicle invasion, PCa stage, higher Gleason score, and biochemical recurrence (BCR). Further analysis showed that the high expression of LAPTM4B-35 was related to the poor overall survival and BCR-free survival of patients with PCa. Multivariate Cox analysis demonstrated that LAPTM4B-35 was an independent prognostic factor for both general survival and BCR-free survival of patients with PCa. Overall, overexpression of LAPTM4B-35 may be associated with tumor progression and poor prognosis in PCa and thus may serve as a new molecular marker to predict the prognosis of PCa patients.

After using miRNA profiling analysis, researchers discovered that miR-188-5p was significantly down-regulated in metastatic PCa. Down-regulation of miR-188-5p is an independent prognostic factor for poor overall and biochemical recurrence-free survival. Restoration of miR-188-5p in PCa cells significantly suppresses proliferation, migration and invasion and inhibits tumour growth and metastasis. LAPTM4B was identified as a direct target of miR-188-5p in PCa, and is found to be significantly over-expressed in PCa. Knockdown of LAPTM4B phenotypically resembles miR-188-5p-induced phenotypes, whereas ectopic expression of LAPTM4B reverses the effects of miR-188-5p. Furthermore, restoration of miR-188-5p can inhibit the PI3K/AKT signaling pathway via the suppression of LAPTM4B. Taken together, these findings may shine light on seeking useful therapeutic target for the development of new anticancer therapy.

Lysosomal degradation is essential for the termination of EGF-stimulated EGF receptor (EGFR) signaling, which requires EGFR sorting to the intraluminal vesicles (ILVs) of multi-vesicular endosomes (MVEs). Researchers showed that LAPTM4B can inhibit EGF-induced EGFR intraluminal sorting and lysosomal degradation, leading to enhanced and prolonged EGFR signaling. LAPTM4B also blocks EGFR sorting by promoting ubiquitination of Hrs (an ESCRT-0 subunit), which inhibits the Hrs association with ubiquitinated EGFR. This phenotype may be counteracted by the endosomal PIP kinase, which directly binds LAPTM4B and neutralizes the inhibitory function of LAPTM4B in EGFR sorting. These results revealed an essential layer of EGFR trafficking regulated by LAPTM4B signaling, and defined a mechanism by which the onco-protein LAPTM4B can transform cells and promote tumor progression.

In one study, researchers explored the effects and mechanisms of LAPTM4B on tumor growth, metastasis and angiogenesis in vitro. RNA interference was used to induce down regulation of LAPTM4B gene expression. RNAi-mediated LAPTM4B knockdown inhibited cell growth and angiogenesis. In vitro, Hela cells with down regulated LAPTM4B also exhibited decreased migration and invasion activity as well as significantly reduced VEGF expression. These results suggested that LAPTM4B inactivation could be a novel therapeutic target for cervical cancer.

References:

Milkereit, R., Persaud, A., Vanoaica, L., Guetg, A., Verrey, F., & Rotin, D. (2015). Laptm4b recruits the lat1-4f2hc leu transporter to lysosomes and promotes mtorc1 activation. Nature Communications, 6(7250), 7250.
Zhang, H., Wei, Q., Liu, R., Qi, S., Liang, P., & Qi, C., et al. (2014). Overexpression of laptm4b-35: a novel marker of poor prognosis of prostate cancer. Plos One, 9(3), e91069.
Zhang, H., Qi, S., Zhang, T., Wang, A., Liu, R., & Guo, J., et al. (2015). Mir-188-5p inhibits tumour growth and metastasis in prostate cancer by repressing laptm4b expression. Oncotarget, 6(8), 6092-104.
Tan, X., Sun, Y., Thapa, N., Liao, Y., Hedman, A. C., & Anderson, R. A. (2015). Laptm4b is a ptdins(4,5)p2 effector that regulates egfr signaling, lysosomal sorting, and degradation. Embo Journal, 34(4), 475-490.
Meng, F., Chen, X., Song, H., & Lou, G. (2015). Laptm4b down regulation inhibits the proliferation, invasion and angiogenesis of hela cells in vitro. Cellular Physiology & Biochemistry International Journal of Experimental Cellular Physiology Biochemistry & Pharmacology, 37(3), 890-900.
Tang, H., Tian, H., Yue, W., Li, L., Li, S., & Gao, C., et al. (2014). Overexpression of laptm4b is correlated with tumor angiogenesis and poor prognosis in non-small cell lung cancer. Medical Oncology, 31(6), 974.

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