LAMTOR2

Official Full Name

late endosomal/lysosomal adaptor, MAPK and MTOR activator 2

Organism

Homo sapiens

Gene ID

28956

Background

The product of this gene is highly conserved with a mouse protein associated with the cytoplasmic face of late endosomes and lysosomes. The mouse protein interacts with MAPK scaffold protein 1, a component of the mitogen-activated protein kinase pathway. In humans, a mutation in this gene has been associated with a primary immunodeficiency syndrome, and suggests a role for this protein in endosomal biogenesis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2009]

Synonyms

p14; ENDAP; ROBLD3; HSPC003; MAPBPIP; MAPKSP1AP; Ragulator2

Cat.No.	Product Name	Price
CSC-DC008536	Panoply™ Human LAMTOR2 Knockdown Stable Cell Line	Inquiry
CSC-SC008536	Panoply™ Human LAMTOR2 Over-expressing Stable Cell Line	Inquiry
CSC-RT2436	Human LAMTOR2 Knockout Cell Line-Hela	Inquiry

Cat.No.	Product Name	Price
AD09005Z	Human LAMTOR2 adenoviral particles	Inquiry
LV16748L	human LAMTOR2 (NM_001145264) lentivirus particles	Inquiry
LV16749L	human LAMTOR2 (NM_014017) lentivirus particles	Inquiry

Cat.No.	Product Name	Price
SHH175079	shRNA set against Mouse Mapbpip(NM_031248.3)	Inquiry
SHH328379	shRNA set against Human LAMTOR2 (NM_014017.3)	Inquiry
SHH328383	shRNA set against Mouse LAMTOR2 (NM_031248.3)	Inquiry
SHH397572	shRNA set against Rat ROBLD3 (NM_001106441.1)	Inquiry
SHW006869	shRNA set against Danio rerio LAMTOR2 (NM_001003549)	Inquiry

Cat.No.	Product Name	Price
CDFH010197	Human LAMTOR2 cDNA Clone(NM_001145264.1)	Inquiry
CDFR006176	Rat Lamtor2 cDNA Clone(NM_001106441.1)	Inquiry
MiUTR1M-06930	LAMTOR2 miRNA 3'UTR clone	Inquiry
MiUTR4H-TG07615	LAMTOR2 miRNA 3'UTR clone	Inquiry
CDCB168344	Danio rerio LAMTOR2 ORF Clone (NM_001003549)	Inquiry
CDCB190277	Rabbit LAMTOR2 ORF clone (XM_002715394.2)	Inquiry
CDCB196259	Rabbit LOC103350196 ORF clone (XM_008265293.1)	Inquiry
CDCL126147	Mouse LAMTOR2 ORF clone (NM_001145264.1)	Inquiry
CDCL130395	Human Mapbpip ORF clone (NM_031248.3)	Inquiry
CDCR007692	Human LAMTOR2 ORF clone(NM_014017.3)	Inquiry
CDCR373228	Rat Lamtor2 ORF Clone(NM_001106441.1)	Inquiry
CDCS418886	Human LAMTOR2 ORF Clone (BC024190)	Inquiry

Detailed Information

Recent Progress

The late endosomal adaptor protein LAMTOR2 is essential for tissue homeostasis by controlling MAPK and mTOR signaling, which in turn regulate cell growth and proliferation, migration and spreading. Moreover, LAMTOR2 critically controls architecture and function of the endocytic system, including epidermal growth factor receptor (EGFR) degradation in lysosomes, positioning of late endosomes and defense against intracellular pathogens.

Cell migration is mediated by the dynamic remodeling of focal adhesions (FAs). Recently, an important role of endosomal signaling in regulation of cell migration was revealed. In the study, researchers showed an essential function for late endosomes carrying the LAMTOR2/3 complex in FA dynamics. LAMTOR2/3-positive endosomes move to the cell periphery along microtubules (MTs) in a Arl8b-dependent manner. They specifically target FAs in order to regulate FA turnover, which is required for cell migration. It was demonstrated that end-directed traffic of LAMTOR2/3-positive endosomes triggered IQGAP1 disassociation from FAs. Taken together, these results suggested that late endosomes contribute to the regulation of cell migration by transporting the LAMTOR2/3 scaffold complex to the vicinity of FAs.

Langerhans cells (LCs) are dendritic cells (DCs) localized to epithelia, where they critically regulate immunity and tolerance. The LAMTOR2 adaptor molecule is part of the late endosomal/LAMTOR complex, thereby contributing to the signal transduction of the extracellular signaling-regulated kinase (ERK) and the mTOR cascade. Mutated and dysfunctional LAMTOR2 leads to a human immunodeficiency disorder with lysosomal defects in immune cells. Given that LAMTOR2 participates in the regulation of endosomal trafficking, growth factor signaling, as well as cell proliferation, researchers investigated the role of LAMTOR2 in mouse DCs/LCs using a conditional knockout mouse model. The LAMTOR2-deficient animals displayed a complete loss of LCs in the epidermis due to impaired proliferation and increased apoptosis of LCs. The related molecular mechanism involves the LAMTOR2-mediated disruption of the LAMTOR complex which results in the malfunction of both ERK and mTOR signal pathways. Hence, it was concluded that LAMTOR2 acts as a novel and essential regulator of LC homeostasis in vivo.

Another group of researchers described the ultrastructural phenotype of the lysosomal system of LAMTOR2-deficient mouse embryonic fibroblasts. Significantly reduced numbers of recycling tubules emanating from maturing multivesicular bodies (MVB) was revealed. These morphological changes in LAMTOR2-deficient cells correlated with the presence of growth factors, but were similarly induced in control cells by inactivating mTOR. Furthermore, proper transferrin receptor trafficking and recycling were needed to form an intact LAMTOR complex. Finally, a severe imbalance in the relative proportions of lysosomes was discovered in LAMTOR2-deficient cells, resulting from increased amounts of mature MVB and lysosomes. These observations suggested that the LAMTOR/Ragulator complex is required not only for maintaining the homeostasis of lysosomal subpopulations but also contributes to the proper formation of MVB-recycling tubules, and regulation of membrane recycling from MVB.

In was demonstrated that CD11c-specific deficiency of LAMTOR2 disrupts LC homeostasis by affecting the LAMTOR-mediated and mTOR signaling. In one study, researchers performed an analysis on LAMTOR2 deficiency specifically in LCs. Langerin-specific ablation of LAMTOR2 caused a complete loss of LCs, accompanied by an increased maturational phenotype. The absence of LCs in LAMTOR2-deficient mice reduced contact hypersensitivity (CHS) responses to the contact sensitizer trinitrochlorobenzene. Further analysis revealed that LAMTOR2 deficiency in DCs/LCs interfered with the LC-relevant transforming growth factor β1 (TGFβ1) pathway, by lowering TGFβ receptor II expression on LCs, along with surface binding of TGFβ1 on BMDCs. Thus it was concluded that LAMTOR2 deficiency affects TGFβ1 sensitivity of LCs, which is mandatory for their homeostasis and subsequently for their immunological function during CHS(Fig.1).

Fig. 1. Microscopic analysis of (green fluorescent) TGFβ1 surface, binding on day 8 CD11c-p14del and control BMDCs. Preincubation with an anti-TGFβ1 blocking antibody was used as negative control. (Sparber et al, 2014)

According to the previous studies, the receptor tyrosine kinase Flt3 and its ligand are crucial for dendritic cell (DC) homeostasis by activating downstream effectors including mTOR signalling. It was shown in mice that conditional ablation of LAMTOR2 in DCs resulted in a severe disturbance of the DC compartment caused by accumulation of Flt3 on the cell surface, which led to an increased downstream activation of the AKT/mTOR signalling pathway and subsequently to a massive expansion of conventional DCs and plasmacytoid DCs in ageing mice. Researchers were also able to revert the symptoms in vivo by inhibiting the activation of Flt3 and its downstream target mTOR.

References:

Schiefermeier, N., Scheffler, J. M., Araujo, M. E. G. D., Stasyk, T., Yordanov, T., & Ebner, H. L., et al. (2014). The late endosomal p14–mp1 (lamtor2/3) complex regulates focal adhesion dynamics during cell migration. Journal of Cell Biology, 205(4), 525-40.
Sparber, F., Scheffler, J. M., Amberg, N., Tripp, C. H., Heib, V., & Hermann, M., et al. (2014). The late endosomal adaptor molecule p14 (lamtor2) represents a novel regulator of langerhans cell homeostasis. Blood, 123(2), 217-227.
Vogel, G. F., Ebner, H. L., De Araujo, M. E. G., Schmiedinger, T., Eiter, O., & Pircher, H., et al. (2015). Ultrastructural morphometry points to a new role for lamtor2 in regulating the endo/lysosomal system. Traffic, 16(6), 617-634.
Sparber F; Tripp CH; Komenda K; Scheffler JM; Clausen BE; Huber LA; Romani N; Stoitzner P. (2015). The late endosomal adaptor molecule p14 (lamtor2) regulates tgfβ1-mediated homeostasis of langerhans cells. Journal of Investigative Dermatology, 135(1), 119-129.
Scheffler, J. M., Sparber, F., Tripp, C. H., Herrmann, C., Humenberger, A., & Blitz, J., et al. (2014). Lamtor2 regulates dendritic cell homeostasis through flt3-dependent mtor signalling. Nature Communications, 5, 5138.
Thauerer, B., Voegele, P., Hermannkleiter, N., Thuille, N., de Araujo, M. E., & Offterdinger, M., et al. (2014). Lamtor2-mediated modulation of ngf/mapk activation kinetics during differentiation of pc12 cells. Plos One, 9(4), e95863.

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