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. Author manuscript; available in PMC: 2015 May 15.
Published in final edited form as: AFCS Nat Mol Pages. 2011 Feb 1;2011:10.1038/mp.a004126.01. doi: 10.1038/mp.a004126.01

ALCAM

Basis Sequence: Mouse

Amanda G Hansen 1, Guido W Swart 2, Andries Zijlstra 1
PMCID: PMC4432864  NIHMSID: NIHMS636446  PMID: 25983661

Protein Function

ALCAM functions as a cell–cell adhesion molecule and engages in homotypic (ALCAM–ALCAM) and heterotypic (ALCAM–CD6) interactions between adjacent cells. These interactions are mediated through its most amino-terminal V domain (D1). In ALCAM-ALCAM interactions this seems to be a D1–D1 interaction (Tanaka et al. 1991; van Kempen et al. 2001), while in ALCAM–CD6 interactions the ALCAM D1 domain binds to the membrane-proximal scavenger receptor cysteine rich (SRCR) domain of CD6 (Bowen et al. 1996). ALCAM is also capable of oligomerizing through lateral interactions between adjacent ALCAM molecules in the same cell. These interactions occur through the D3–D5 domains proximal to the membrane (van Kempen et al. 2001). ALCAM expression is most apparent at areas of cell–cell contact, where it may interact with other cell–cell adhesion molecules. In fact, upon reconstitution of the α-catenin/E-cadherin complex by α-N-catenin transfection, ALCAM relocalizes to the cell membrane and co-localizes with E-cadherin at the cell membrane in prostate cancer cells. In addition, these cells reverted to an epithelial-like morphology (Tomita et al. 2000) further defining a functional role for ALCAM in cell–cell adhesion. The amino-terminal V-type Ig domain is required for cell–cell adhesive interactions and is, in fact, expressed as an isolated, alternatively spliced isoform (Ikeda and Quertermous 2004).

While the participation of ALCAM in several biological processes has been verified, the exact molecular mechanism remains unclear. The highly conserved nature of the short cytoplasmic domain suggests that ALCAM functions, in part, by conveying extracellular signals to the cytoplasm. Although named primarily for its role in leukocytes, ALCAM exhibits broad expression including neuronal tissues, epithelial cells, and hematopoietic progenitor cells. In spite of the participation of ALCAM in many biological processes, ALCAM knockout mice are viable, fertile and have no outward visible defects. A full analysis of the literature requires consideration of all its alternate names, including CD166, MEMD, SC-1, BEN, GRASP, DM-GRASP, HCA, and SB-10.

ALCAM in hematopoietic cells

ALCAM received this name when it was identified in activated leukocytes as the only known ligand for CD6 (Bowen et al. 1995), and the ALCAM–CD6 interaction is required for optimal activation of T-cells (Gimferrer et al. 2004; Hassan et al. 2006; Singer et al. 1996; Zimmerman et al. 2006). Moreover, ALCAM plays a critical role in mediating the transmigration of T-cells and monocytes across the blood–brain barrier (Cayrol et al. 2008; Lee and Imhof 2008). Through its heterotypic interaction with CD6, ALCAM seems to be important for formation of the immunological synapse at the T-cell:antigen-presenting cell (APC) interface during antigen presentation (Castro et al. 2007). In fact, optimal T-cell activation requires CD6–ALCAM engagement (Hassan et al. 2004; Hassan et al. 2006). Moreover, unlike other adhesion molecules in the immunological synapse, ALCAM is required for the whole process of T-cell activation (Zimmerman et al. 2006).

ALCAM in development

ALCAM is expressed in human blastocysts, but not in embryos at the 8-cell or morula stages. ALCAM expression reappears in most developing tissues (Diekmann and Stuermer 2009; Fraboulet et al. 2000; Hirata et al. 2006; Pourquié et al. 1992). Nevertheless, the adhesive role of ALCAM is apparent in development, where the loss of ALCAM function results in loss of cell adhesion and cardiac morphogenesis in the Xenopus model system (Gessert et al. 2008). ALCAM functions in hematopoietic and endothelial development and is highly associated with hematopoiesis and vasculogenesis (Ohneda et al. 2001). Neuronal outgrowth studies in chick and zebra fish further define ALCAM as a guidance protein for cellular migration and neuronal outgrowth during development (Diekmann and Stuermer 2009; Heffron and Golden 2000; Ott et al. 2001).

ALCAM in multipotent and stem cells

Although ALCAM was initially used to delineate hematopoietic stem cells (Ohneda et al. 2001), the molecule has been used broadly as a surface marker (under the name CD166) in a panel of markers (including CD44, CD90, CD105, CD73, CD29 and CD133) to define multipotent cells from a variety of tissues, including umbilical cord blood (Prat-Vidal et al. 2007), bone marrow (Liu et al. 2008), testes (Gonzalez et al. 2009), fetal lung (Hua et al. 2009), intervertebral disc (Risbud et al. 2007), and dental pulp (Karaöz et al. 2010). More recently, the expression of CD166 as a marker of cancer stem cells has become of significant interest (Dalerba et al. 2007; Horst et al. 2009; Stuelten et al. 2010). While ALCAM is clearly a defining feature of stem cells, it is unclear if there is a functional contribution to the multipotent capacity of these cells.

ALCAM in the neural network

The abundance of ALCAM in neuronal tissue is reflected in its sequential discovery in neurons and related tissues from various species as DM-GRASP (Burns et al. 1991), SC-1 (Tanaka et al. 1991), neurolin (Paschke et al. 1992), and BEN (Corbel et al. 1992). ALCAM controls the extension of axons (Avci et al. 2004; DeBernardo and Chang 1995; Ott et al. 2001; Pollerberg and Mack 1994) and is involved in axonal guidance and mapping (Buhusi et al. 2009; Ott et al. 1998). While ALCAM knockout mice are outwardly normal in appearance, they do have physiological deficiencies, including a delay in maturation of neuromuscular junctions and defects in axon fasciculation (Buhusi et al. 2009; Weiner et al. 2004). ALCAM-blocking antibodies induce aberrant branching in zebra fish motor axons during development (Ott et al. 2001). During in vitro experiments axon outgrowth can be guided by ALCAM-coated surfaces, thereby providing conclusive evidence of ALCAM as a migration-guiding factor (Avci et al. 2004; DeBernardo and Chang 1995).

ALCAM in cancer

Cancer-associated ALCAM was first identified as MEMD in melanoma cell lines (Degen et al. 1998). ALCAM has subsequently been found to be expressed in almost all cancers, although it is distinctly absent in myeloma. Although the pathological function of ALCAM is not fully understood, in vivo mouse studies demonstrate its participation in cancer progression (Choi et al. 2000; Lunter et al. 2005; van Kempen et al. 2004). Truncation of ALCAM can be achieved by ADAM17 and may facilitate migration (Rosso et al. 2007). Indeed the upregulation of truncated ALCAM that lacks the D1 domain (ΔN-ALCAM) promotes metastasis, while the ectopic expression of soluble amino-terminal D1 (V) domain inhibits metastasis (Lunter et al. 2005; van Kilsdonk et al. 2008). The distinct upregulation of ALCAM in some cancers but downregulation in others has created a paradox in terms of its contribution to cancer progression (Ofori-Acquah and King 2008). Histological analysis has emphasized that the cytoplasmic localization of ALCAM correlates more strongly with cancer progression than the overall expression level (Kahlert et al. 2009; Sawhney et al. 2009; Mezzanzanica et al. 2008; Burkhardt et al. 2006). Although somewhat contradictory, recent research using blocking antibodies confirms that the presence of ALCAM can contribute to the metastatic process (Wiiger et al. 2010; Kahlert et al. 2009), while expression analysis illustrates that the absence of ALCAM can convey resistance to treatment (Ihnen et al. 2010). It is likely that the role of ALCAM in cancer depends on the tissue from which the tumor developed.

ALCAM expression has been used increasingly as a biomarker of cancer progression in prostate cancer (Kristiansen et al. 2005), colorectal cancer (Weichert et al. 2004), breast cancer (Davies and Jiang 2010; Davies et al. 2008; Ihnen et al. 2010), oral cancers (Sawhney et al. 2009; van den Brand et al. 2010), pancreatic cancer (Kahlert et al. 2009), neuroblastoma (Corrias et al. 2010), ovarian cancer (Mezzanzanica et al. 2008), and melanoma (van Kempen et al. 2000). Serum levels of ALCAM are also explored as a diagnostic tool for cancer (Hong et al. 2010; Kulasingam et al. 2009; Vaisocherová et al. 2009).

ALCAM in the bone marrow

ALCAM was defined initially as a hematopoietic cell antigen present in bone marrow (Bruder et al. 1997; Uchida et al. 1997). Indeed, ALCAM is a surface marker of the earliest hematopoietic precursor populations, the mesenchymal stem cells, and stromal cell populations present in the bone (Bruder et al. 1998; Cortés et al. 1999; Nakamura et al. 2010). Along with CD90 and CD105, ALCAM defines a multipotent progenitor cell population capable of chondrogenic, osteogenic and adipogenic differentiation (Choi et al. 2008; Delorme and Charbord 2007; Stewart et al. 2003). Early observations by Bruder et al. indicated a functional role for ALCAM in the bone marrow. They determined that anti-ALCAM fragment, antigen binding (Fab) fragments promote osteogenic differentiation (Bruder et al. 1998). Indeed ALCAM delineates subpopulations of the endosteal niche, where its expression defines populations of mature osteoblasts and mesenchymal stem cells (Arai et al. 2002; Chitteti et al. 2010; Nakamura et al. 2010). In particular, Chitteti et al. defined mature osteoblasts specifically as CD45−CD31−Ter119−Sca1−ALCAM+ (Chitteti et al. 2010).

Regulation of Activity

Since cell–cell adhesion is the primary activity of ALCAM, this can be regulated by its availability and ability to bind to proximal partners. ALCAM is dysregulated in a number of cancers, including, but not limited to, melanoma, colorectal, breast and prostate. Immunohistochemical analysis showed that ALCAM was overexpressed in low-grade carcinoma. However, in some high grade carcinomas ALCAM was either localized to the cytoplasm or lost altogether (Burkhardt et al. 2006; Kristiansen et al. 2003; Mezzanzanica et al. 2008; Zheng et al. 2004). Although there is differential ALCAM expression in cancer, the mechanism by which it is regulated is unknown.

At the subcellular level, cytoskeleton disruption via chemical treatment in erythroleukemic K562 cells with cytochalasin D promotes lateral movement of ALCAM and promotes ALCAM-mediated adhesion regulated through cytoskeleton-dependent clustering (Nelissen et al. 2000), suggesting ALCAM clustering is necessary to form stable cell adhesion complexes (van Kempen et al. 2001; van Kilsdonk et al. 2008).

ALCAM can be shed from the cell surface. Currently ADAM17, a member of the disintegrin and metalloproteinase family, is the only known protease able to cleave ALCAM (Bech-Serra et al. 2006). Cleavage of ALCAM is thought to occur at the membrane proximal region, generating a soluble ALCAM component containing the five extracellular domains and a truncated membrane-bound ALCAM containing the transmembrane and cytoplasmic domains. Lastly, the expression of the soluble D1 domain (sALCAM, the most amino-terminal V domain) (Ikeda and Quertermous 2004) could potentially disrupt the interaction between full-length membrane-anchored ALCAM molecules (van Kilsdonk et al. 2008).

Interactions with Ligands and Other Proteins

In addition to the well established homophilic interactions, ALCAM was identified as the only known ligand for CD6, a member of the SRCR protein superfamily (Bowen et al. 1995; van Kempen et al. 2001). In contrast with the relatively weak and transient homophilic ALCAM–ALCAM interactions, ALCAM–CD6 interactions are robust and persistent (Hassan et al. 2004; Te Riet et al. 2007). These interactions are thought to be important for T-cell proliferation and maturation (Zimmerman et al. 2006). In both instances it is the amino-terminal V domain that is engaged in the protein–protein interactions. For neuronal guidance, ALCAM has been suggested to interact with L1CAM (L1-cellular adhesion molecule, also known by the chick homolog NgCAM). This interaction seems to target retinal axons during development (Avci et al. 2004; Buhusi et al. 2009; DeBernardo and Chang 1996).

ALCAM co-localizes with E-cadherin through an α-catenin-dependent process, although no direct interaction has been confirmed (Tomita et al. 2000). ALCAM also requires active protein kinase C α (PKC-α) for ALCAM-mediated cell adhesion. However, no physical association between these proteins has been confirmed (Zimmerman et al. 2004). Association with the actin cytoskeleton is confirmed and regulates ALCAM clustering. The interactions that connect ALCAM to the cytoskeleton are unknown (Nelissen et al. 2000; Te Riet et al. 2007), although preliminary findings from Sawhney et al. (2009) suggest the scaffolding proteins 14-3-3ζ and 14-3-3σ may be involved.

The cytoplasmic tail has only been documented to interact with ubiquitin. Ubiquitination seems to control ALCAM endocytosis and thereby affect its role in axon navigation (Thelen et al. 2008).

ALCAM was also shown to interact with EGFR (Wu et al. 2006); however, this observation was made in an epidermoid carcinoma cell line (A431) and has not been confirmed elsewhere.

Recently, ALCAM was shown to specifically bind galectin-8 sequestered in the extracellular matrix (Cárdenas Delgado et al. 2010). This interaction influenced endothelial cell migration and tubule morphogenesis. Anti-ALCAM antibody studies suggest that this interaction involves the same domain that is required for homotypic ALCAM–ALCAM, as well as CD6, binding.

Regulation of Concentration

ALCAM concentrations in the cell can be regulated by expression, endocytosis, and shedding from the cell surface. No defined studies have been found that define ALCAM expression and the regulation of its promoter. ALCAM endocytosis seems to be regulated by ubiquitination (Thelen et al. 2008). Shedding of the molecule is possible through ADAM17 (Rosso et al. 2007).

Subcellular Localization

On the cell surface in the blood–brain barrier endothelium, ALCAM is concentrated in cholesterol-enriched microdomains, or lipid rafts (Cayrol et al. 2008). In highly specialized lung microvascular endothelial cells, ALCAM is localized to the adherence junctions, and participates in a complex containing vascular endothelial (VE) cadherin and neural (N) cadherin (Ofori-Acquah and King 2008). ALCAM is continuously recycled through endocytic pathways and is readily detectable in early endosomes. On the cell surface, ALCAM co-localizes with clathrin, but not caveolin-1 (Piazza et al. 2005). In several neoplasia, ALCAM overexpression is associated with diffuse cytoplasmic staining (Burkhardt et al. 2006; Sawhney et al. 2009; Weichert et al. 2004).

Major Sites of Expression

ALCAM is expressed in most epithelial cells, hematopoietic cell populations (particularly activated T-cells), the central nervous system, endothelial cells, and most stem cell populations.

Phenotypes

ALCAM knockout mice have been generated. These mice exhibit no defects in fertility, nor any outward physiological defects, and have normal organ development and a normal lifespan (Weiner et al. 2004). However, upon detailed analysis, an axon fasciculation defect and a neuromuscular synapse defect have been identified (Buhusi et al. 2009). It seems that ALCAM is required for targeting retinal axons to their termination zones in two brain targets: the superior colliculus and the lateral geniculate nucleus (Buhusi et al. 2009).

Splice Variants

Currently, soluble ALCAM (sALCAM, the most amino-terminal V domain) is the only known isoform (Ikeda and Quertermous 2004).

Antibodies

The ALCAM antibodies AZN-L50 (Nelissen et al. 2000) and A8 (Buckley et al. 2005) were reported.

The anti-ALCAM antibody HPA010926 was also characterized by the Human Protein Atlas project and is available through Sigma (US) or Atlas Antibodies (Europe).

Other defined antibodies that are commercially available with their application are listed below:

R&D Systems anti-ALCAM (Clone 105902)

Mouse Monoclonal Biotin-Conjugated, Human

Western blot, Flow Cytometry

LifeSpan Biosciences anti-CD166 (3A6)

Mouse Monoclonal

LifeSpan Biosciences anti-CD166 (7H119)

Mouse Monoclonal (Biotin), Human

Immunohistochemistry (IHC)

Santa Cruz Biotechnology, anti-ALCAM (3H1929)

Mouse Monoclonal, Human

Flow Cytometry

Santa Cruz Biotechnology anti-ALCAM (6A66)

Mouse Monoclonal, Human/rat

Immunoprecipitation (IP), Immunocytochemistry

Millipore, anti-CD166 (Clone 3A6)

Mouse Monoclonal, Human

IP, IHC, Flow Cytometry, Enzyme-linked immunosorbent assay

Vector Lab. Cat. No. VP-C375

Mouse Monoclonal (clone MOG/07)

Western blot, IHC

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