LAPTM4B: an oncogene in various solid tumors and its functions

Abstract

The oncogene Lysosome-associated protein transmembrane-4β (LAPTM4B) gene was identified, and the polymorphism region in the 5'-UTR of this gene was certified to be associated with tumor susceptibility. LAPTM4B-35 protein was found to be highly expressed in various solid tumors and could be a poor prognosis marker. The functions of LAPTM4B in solid tumors were also explored. It is suggested that LAPTM4B could promote the proliferation of tumor cells, boost invasion and metastasis, resist apoptosis, initiate autophagy and assist drug resistance.

Figure 1

Topology of LAPTM4B-24 (left) and LAPTM4B-35 (right) proteins. N encircled by a hexagon represents N-glycosylation site; P encircled by a circle represents phosphorylation site.

Figure 2

The expression levels of LAPTM4B mRNA in human normal tissues. The asterisk represents the organ in which LAPTM4B is highly expressed in fetal tissues.

Figure 3

Schematic representation of the LAPTM4B promoter and exon 1. Exon 1 is depicted as a box; the gray box indicates the 19- bp sequence. ATG loci are shown, respectively. The nucleotide sequence is numbered with transcriptional start site as +1. Allele *1 contains only one copy of the 19-bp sequence; meanwhile, allele *2 contains two copies of the 19- bp sequence in a tandem array.

Figure 4

Comparison of the putative proteins encoded by LAPTM4B *1 and LAPTM4B *2. This schematic diagram shows the partial segments of the first exon in LAPTM4B *1 (a) and LAPTM4B *2 (b). The sequence numbers of the first nucleotide (left) and the final amino acid (right) in each row are shown, respectively. The nucleotide sequences are numbered with the putative transcription start site marked as +1. In-frame termination codons are underlined and marked by the symbol #, and the 19-bp sequences in both of the alleles are represented in italics. The mRNA of allele *1 can start translation only at nucleotide 157, because of the in-frame termination codons at nucleotides 40 and 103. However, allele *2 starts translation at nucleotide 17, producing an extra 53 amino acids, which are boxed at the N terminus of LAPTM4B.

Figure 5

Summary of the mechanisms for LAPTM4B promoting cancer development. (a) LAPTM4B inhibits the function of Hrs so that EGF-stimulated EGFR signaling can be prolonged and finally promotes cell proliferation and chemotherapy resistance, by enhancing the ubiquitination of Hrs by the E3 ubiquitin ligase Nedd4. (b) Inactive EGFR and LAPTM4B recruited exocyst subcomplex containing Sec5 to promote the association of EGFR with autophagy inhibitor Rubicon, which in turn dissociated Beclin1 to start autophagy. (c) Cells with high levels of LAPTM4B expression displayed increased clearance of ceramide from late endosome, which makes late endosome membranes stable and cells insensitive to lysosome-mediated death. (d) LAPTM4B activates the PI3K/AKT signaling pathway by its PPRP motif. The active AKT makes the glycogen synthase kinase -3β phosphorylated, which attenuates the phosphorylation of c-Myc and results in the accumulation of c-Myc. The active AKT also phosphorylates FOXO4, resulting in transcription failure of p27 gene. (e) LAPTM4B motivates multidrug resistance through efflux by interaction with P-glycoprotein and activating PI3K/AKT signaling. However, LAPTM4B-overexpressing cells do not have a high expression of P-glycoprotein, and hence further research is needed regarding this mechanism. (f) Overexpression of LAPTM4B leads to overexpression of MMP-2 or MMP-9, and the PPRP motif of LAPTM4B can interact with SH3 domain-containing signaling proteins related with invasion and metastasis; however, the specific mechanism should be explored in a further step.