Cells have receptor proteins on their surface that enable them to detect changes in their environment and communicate with other cells. Signal molecules bind to a segment of the receptor called the extracellular domain that faces out from the cell. This can result in the activation of another domain in the receptor that is just inside the cell, which, in turn, activates signaling pathways that relay the information around the cell.

However, these communication systems are often disrupted in cancer cells. This helps the cells to override the strict growth controls imposed upon them by other (healthy) cells in the body. The gene that encodes a receptor protein called Anaplastic Lymphoma Kinase (or ALK for short) is often mutated in some types of human cancer so that the protein is always active. However, we still do not know what signal molecules bind to the ALK protein to activate it in normal cells.

Guan, Umapathy et al. used a variety of cell biology and biochemical techniques to study the role of ALK. The experiments show that when either of two proteins called FAM150A and FAM150B are produced in rat nerve cells alongside ALK, the nerve cells rapidly respond and form outgrowths. Experiments using cancer cells derived from human nerve cells also yielded similar results. Guan, Umapathy et al. found that the extracellular domain of ALK can physically interact with FAM150A and FAM150B.

The eyes of fruit flies that had been genetically modified to produce the human ALK protein alongside either FAM150A or FAM150B grew more than normal, giving the eyes an abnormal "rough" appearance. Further experiments showed that FAM150A and FAM150B are also able to increase the level of activation of an ALK mutant protein that is already active. Therefore, in future, the development of drugs that stop FAM150A and FAM150B from binding to ALK may be useful for treating cancers that are driven by high levels of ALK activity. Many challenging questions lie ahead to better understand how FAM150A and FAM150B interact with ALK.

Activation of anaplastic lymphoma kinase (ALK) is commonly due to fusion of the ALK kinase domain with a dimerization partner that drives activation, however, ALK activation also occurs in the context of the full length receptor, for example, as activating point mutations in neuroblastoma (Maris et al., 2007; Carén et al., 2008; Chen et al., 2008; George et al., 2008; Janoueix-Lerosey et al., 2008; Mosseé et al., 2008; Hallberg and Palmer, 2013). In many additional tumor types ALK overexpression and activation has been described, and it is unclear whether this is dependent on the activity of a ligand (Hallberg and Palmer 2013). The ALK receptors in both Drosophila and Caenorhabditis elegans have well defined ligands – Jeb (Englund et al., 2003; Lee et al., 2003; Stute et al., 2004) and HEN-1 (Ishihara et al., 2002), respectively. In contrast, vertebrate ALK has long been considered as an orphan receptor.

The human ALK locus encodes a classical receptor tyrosine kinase (RTK) comprising a unique extracellular ligand-binding domain, a transmembrane domain and an intracellular tyrosine kinase domain (Hallberg and Palmer, 2013). The extracellular portion of ALK which contains two MAM domains (named after meprin, A-5 protein and receptor protein tyrosine phosphatase μ), a glycine-rich region (GR) and a LDLa domain, is unique among the RTKs. ALK, and the related leukocyte tyrosine kinase (LTK) RTK, share kinase domain similarities as well as a GR in the membrane proximal portion of their extracellular domains (ECDs) (Iwahara et al., 1997; Morris et al., 1997). Recent screening of the extracellular proteome identified two novel secreted proteins as ligands for LTK – family with sequence similarity 150A (FAM150A) and family with sequence similarity 150B (FAM150B). Both bind to the ECD of the receptor leading to activation of downstream signaling in cell culture models (Zhang et al., 2014). FAM150A and FAM150B are unique, displaying homology only with one another but not with any other proteins in mammals (Zhang et al., 2014). Furthermore, we found the reported strong expression of FAM150B in the human adrenal gland (Zhang et al., 2014) intriguing, given the role of ALK in neuroblastoma.

Here we report the identification of FAM150A and FAM150B as potent ligands for human ALK. We investigated ALK activation by FAM150A and FAM150B proteins in PC12 cell neurite outgrowth assays where we observed a strong activation of ALK signaling. Conditioned medium containing either FAM150A or FAM150B was able to activate endogenous ALK signaling in neuroblastoma cells. We also employed the model organism Drosophila melanogaster as a readout for activation of ALK by FAM150A and FAM150B, showing that FAM150 proteins are able to robustly drive human ALK activation when ectopically coexpressed in the fly. FAM150A and FAM150B bind to the ECD of ALK and, in addition to activation of wild-type ALK, are able to drive ‘superactivation’ of activated ALK mutants from neuroblastoma. The GR of the ALK receptor ECD is important for FAM150 activation, and monoclonal antibodies (mAb) recognizing the GR of ALK are able to inhibit activation of ALK by FAM150A. In conclusion, our data show that ALK is robustly activated by FAM150A/B finally providing an answer to the identity of the elusive ligands for this RTK.

ALK and the related LTK share similarity in their membrane proximal ECD in the form of a glycine-rich domain that is ∼250 amino acids in length (Figure 1A, GR depicted in grey). This domain contains multiple runs of up to eight glycine residues, and is unique to ALK and LTK within the human genome. The importance of the GR in ALK has been highlighted in Drosophila studies, where four independent point mutations leading to exchange of single glycine residues result in complete loss of function in vivo (Englund et al., 2003) (Figure 1—figure supplement 1). The similarity between ALK and LTK within the GR is ∼70%, with amino acid identity of 55%, containing a total of 51 conserved glycine residues (Figure 1B). Given this similarity, and the important role of the glycine-rich domain for function in Drosophila, we hypothesized that FAM150A and FAM150B, which were recently reported as ligands for LTK (Zhang et al., 2014) may act as ligands for ALK.

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In order to initially test whether FAM150A or FAM150B could activate ALK we assayed neurite outgrowth activity in PC12 cells. Expression of either FAM150A, or FAM150B or ALK alone, did not lead to activation. This was in contrast to the strong activation seen with the positive control ALK-F1174L which is a well characterized constitutively active ALK neuroblastoma mutation. However, coexpression with either FAM150A or FAM150B led to robust activation of ALK neurite outgrowth activity (Figure 1C, quantified in 1D). This ALK activation was visualized by phosphorylation of Y1604 in the tail of the ALK intracellular domain (Figure 1E, F; Figure 1—figure supplement 2) and was further associated with stimulation of downstream signaling such as the phosphorylation of the downstream target ERK1/2 (Figure 1E, F). Thus in PC12 cells FAM150A and FAM150B act to stimulate signaling via the wild-type ALK receptor, in a manner that leads to phosphorylation of the ALK receptor.

We next tested the ability of exogenously produced FAM150A or FAM150B to activate ALK, employing medium conditioned with FAM150A or FAM150B to activate PC12 cells expressing ALK. Addition of conditioned medium from cells expressing FAM150A or FAM150B led to strong activation of ALK in receiving cells that expressed ALK, as measured by neurite outgrowth and activation of downstream signaling (Figure 2A, B). We then examined whether ALK signaling activity induced by either FAM150A or FAM150B was sensitive to ALK inhibition, employing the ALK inhibitor crizotinib (Zou et al., 2007). We observed that ALK activation by FAM150A or FAM150B was inhibited by addition of 250 nM crizotinib (Figure 2A, B).

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To address whether endogenous levels of ALK responded to medium conditioned with either FAM150A or FAM150B, we employed the IMR-32 neuroblastoma cell line that expresses wild-type ALK. Once again, we observed robust activation of ALK by the addition of either FAM150A-containing or FAM150B-containing conditioned medium, employing pALK-Y1604 and pERK1/2 as readout (Figure 2C). The activation of ALK and downstream signaling events in IMR-32 cells were effectively blocked by the addition of 250 nM crizotinib (Figure 2C). The activation of exogenous ALK in PC12 cells or endogenous ALK in IMR-32 cells was reproduced with the addition of recombinant FAM150A purified from Sf21 cells (Figure 2D). Unfortunately we could not produce sufficient amounts of recombinant FAM150B protein, precluding a similar analysis with FAM150B.

More careful examination of ALK activation by FAM150A or FAM150B containing conditioned media in IMR-32 cells revealed activation of signaling at 2–5 min, peaking around 20 min before decreasing at later time points. This response was observed at the level of ALK receptor phosphorylation (pALK-Y1604), and with downstream pERK5 (Umapathy et al., 2014) and pERK1/2 (Figure 2E, F). Here we employed antibodies recognizing pALK-Y1604, allowing differentiation of ALK activation in IMR-32 cells from that of LTK (Figure 1—figure supplement 2). Thus we observed that exogenously produced FAM150A and FAM150B proteins stimulate ALK signaling in both PC12 cells and IMR-32 cells. We also examined potential modulation of ALK activation by FAM150A/B upon addition of heparin, which has recently been reported to activate ALK (Murray et al., 2015). While we were able to see strong binding of purified FAM150A protein as well as FAM150A-HA and FAM150B-HA from conditioned medium to heparin-agarose, we did not observe any additional activation of ALK by FAM150 proteins in the presence of heparin (Figure 2—figure supplement 1; Figure 2—figure supplement 2).

We next analyzed the ability of FAM150A or FAM150B to activate human ALK in a Drosophila model, which offers a clear readout. Neither the Drosophila Alk ligand Jeb (Englund et al., 2003; Lee et al., 2003; Stute et al., 2004) nor previously proposed vertebrate ligands, that is, human midkine (MDK) and pleiotrophin (PTN) are able to activate either mouse or human ALK (Yang et al., 2007; Hugosson et al., 2014). Expression of either FAM150A or FAM150B in the developing eye, using the GMR-Gal4 driver, resulted in normal eye morphology (Figure 3A). In contrast, expression of constitutively active ALK-F1174S described in neuroblastoma patients results in a rough eye morphology (Figure 3A) (Martinsson et al., 2011), while no eye phenotype was observed upon the expression of wild-type human ALK alone (Figure 3A) (Martinsson et al., 2011, Schonherr, Ruuth et al., 2011, Schonherr, Ruuth et al., 2011, Chand et al., 2013; Hugosson et al., 2014). This can be compared with coexpression of either FAM150A or FAM150B together with human ALK which led to a rough eye phenotype, proving that both FAM150A and FAM150B were able to activate human ALK in this in vivo system (Figure 3A, B).

Figure 3

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We next examined binding of the human ALK ECD with purified FAM150A by ELISA and Biacore surface plasmon resonance (SPR) analysis. Both ELISA and Biacore analysis showed that FAM150A binds specifically to the ALK ECD (Figure 4A; Figure 4—figure supplement 1). Purified human FAM150A (Zhang et al., 2014) binds to ALK-ECD-Fc with a dissociation constant of ∼20 nM (Figure 4A). We also examined the ability of either FAM150A or FAM150B to bind human ALK by immunoprecipitation and immunofluorescence analysis (Figure 4B–D). Here we observed that both FAM150A and FAM150B could be independently immunoprecipitated with the ALK receptor, and that ALK could be immunoprecipitated with either FAM150A or FAM150B in the reciprocal pull-down experiments (Figure 4B, C; Figure 4—figure supplement 2). Since FAM150A/B also bind LTK, we asked whether ALK and LTK interacted in the presence of FAM150A. Indeed, both ALK and FAM150A were found to immunoprecipitate with LTK (Figure 4—figure supplement 3). Immunofluorescence analysis of cells expressing human ALK confirmed these findings, with clear association of both HA-tagged FAM150A and HA-tagged FAM150B with ALK expressing cells observed (Figure 4D). In these experiments we observed uptake of FAM150A and FAM150B into ALK-positive intracellular vesicles, suggesting that binding to ALK on the cell surface leads to uptake and internalization of the ALK-FAM150 complex (Figure 4D).

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We further examined the role of the GR of ALK in FAM150A/B binding. Deletion of the GR in the ALK ECD did not affect FAM150A binding but led to loss of FAM150B binding (Figure 4—figure supplement 4). Given the importance of the GR of ALK in Drosophila (Englund et al., 2003) (Figure 1—figure supplement 1), we mutated these conserved residues in human ALK (G740D, G823D, G893E and G934D) and tested their effect on the FAM150-ALK interaction. Despite being well expressed, all four glycine mutations in the GR severely impaired binding of FAM150B to ALK. Consistent with our earlier results we were unable to see any effect of mutation of individual glycine on the FAM150A-ALK interaction (Figure 4—figure supplement 5).

In previous work, we and others have generated antibodies to the ECD of ALK (Moog-Lutz et al., 2005, Witek et al., 2015). We investigated whether any of these antibodies recognized the GR in the ALK ECD, and were able to identify three interesting candidates (anti-ALK mAb13, mAb48 and mAb135, Figure 4—figure supplement 6). These antibodies were next tested for their ability to modulate the activation of ALK by purified FAM150A. While mAb135 had no effect on FAM150A activation of ALK, we observed that mAb13 exhibited strong inhibition of FAM150A-induced ALK activation (Figure 4E), while mAb48 robustly activated ALK in the absence of FAM150A ligand (Figure 4E). Taken together, these data strongly support a role for the GR in the activation of ALK by FAM150 proteins.

In cell lines as well as in the Drosophila model, we observed extremely high levels of ALK activation when compared even with highly active ALK mutants such as ALK-F1174S, suggesting the possibility that these already active mutants can be activated to a higher level in the presence of a potent ligand. Therefore, we examined the ability of either FAM150A or FAM150B to ‘superactivate’ already active ALK mutants as described in neuroblastoma. In PC12 cells we indeed observed activation of the ALK-R1275Q mutant to a higher level, as evidenced by increased pERK1/2 and in neurite outgrowth assays (Figure 4F). A similar effect was observed with the ALK-F1174L mutant (Figure 4—figure supplement 7). This increased activity was also seen in CLB-GAR cells, which endogenously express the ALK-R1275Q mutant, with increased activation of ERK1/2 upon the addition of either FAM150A or FAM150B (Figure 4G).

In conclusion, our work identifies FAM150A and FAM150B as novel ligands that bind and activate the human ALK RTK. The identity of a ligand(s) for vertebrate ALK has been an evolving question for many years, with a number of reports over the past 15 years examining the role of the small heparin binding growth factors MDK and PTN as ligands for vertebrate ALK (Stoica et al., 2001; Stoica et al., 2002). However, a number of independent studies including our own work have presented convincing evidence that MDK and PTN do not activate ALK (Motegi et al., 2004; Moog-Lutz et al., 2005; Mourali et al., 2006; Mathivet et al., 2007; Hugosson et al., 2014; Murray et al., 2015). The recent identification of long chain heparins as activators of ALK in neuroblastoma cells (Murray et al., 2015) and the interplay of this with ALK activation by FAM150A and FAM150B will require further work. FAM150A and FAM150B are very basic proteins; FAM150A has a predicted pI of 10.6, while FAM150B has one of 9.75, and we show here that FAM150A exhibits heparin binding properties, however we have not observed a cooperative role of heparin and the FAM150 ligands in ALK activation as has been described for the fibroblast growth factor receptors and FGF. Our data also suggest that FAM150 ligands can bind an ALK-LTK heterodimer complex. While the physiological significance of such an interaction is currently unclear, ALK and LTK have been reported to be coexpressed in some tissues, such as the mouse hippocampus (Weiss et al., 2012), where such an interaction may be important.

FAM150 proteins do not seem to be conserved outside the vertebrates. In zebrafish there are three FAM150 proteins (FAM150ba, FAM150bb and FAM150A), while in mouse and humans only FAM150A and FAM150B exist (Zhang et al., 2014). In invertebrate model organisms the ALK ligands, Jeb in Drosophila and HEN-1 in C. elegans, do not appear to resemble the FAM150A/B ligands. The Drosophila Jeb ligand is unable to activate either mouse or human ALK (Yang et al., 2007), and to date, no Jeb-like ligand for vertebrate ALKs has been reported. The evolution of the FAM150 proteins as ALK ligands is an interesting topic for further investigation.

In the case of ALK mutations that are ligand dependent, as well as in situations where the ALK receptor is overexpressed, such as in neuroblastoma, the mechanisms by which ALK is activated is fundamental for understanding their role in tumor development. Here the identification of ALK ligands will allow a more rigorous interrogation of ALK signaling in these scenarios. The finding that FAM150A and FAM150B are not only able to activate the wild-type receptor, but also to ‘superactivate’ mutant ALK receptors, is important in this context. These findings, together with the observed expression pattern of FAM150A and FAM150B in adrenal gland and thyroid and the inhibition of ALK activation by FAM150A with monoclonal antibodies shown here, suggest that a future potential therapeutic arm may involve agents that interfere with FAM150A/B activation of ALK offering additional therapeutic approaches in patients with neuroblastoma for which single drug treatments targeting ALK have had limited effect to date.

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Author details

1. Jikui Guan

   Department of Medical Biochemistry and Cell Biology, Instititute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

   Contribution

   JG, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Contributed equally with

   Ganesh Umapathy

   Competing interests

   The author declares that no competing interests exist.

2. Ganesh Umapathy

   Department of Medical Biochemistry and Cell Biology, Instititute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

   Contribution

   GU, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Contributed equally with

   Jikui Guan

   Competing interests

   The author declares that no competing interests exist.

3. Yasuo Yamazaki

   Department of Medical Biochemistry and Cell Biology, Instititute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

   Contribution

   YY, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The author declares that no competing interests exist.

4. Georg Wolfstetter

   Department of Medical Biochemistry and Cell Biology, Instititute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

   Contribution

   GW, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The author declares that no competing interests exist.

5. Patricia Mendoza

   Department of Medical Biochemistry and Cell Biology, Instititute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

   Contribution

   PM, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The author declares that no competing interests exist.

6. Kathrin Pfeifer

   Department of Medical Biochemistry and Cell Biology, Instititute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

   Contribution

   KP, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The author declares that no competing interests exist.

7. Ateequrrahman Mohammed

   Department of Medical Biochemistry and Cell Biology, Instititute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

   Contribution

   AM, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The author declares that no competing interests exist.

8. Fredrik Hugosson

   Department of Medical Biochemistry and Cell Biology, Instititute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

   Contribution

   FH, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The author declares that no competing interests exist.

9. Hongbing Zhang

   Five Prime Therapeutics Inc., South San Francisco, United States

   Contribution

   HZ, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The author declares that no competing interests exist.

10. Amy W Hsu

    Five Prime Therapeutics Inc., South San Francisco, United States

    Contribution

    AWH, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

    Competing interests

    The author declares that no competing interests exist.

11. Robert Halenbeck

    Five Prime Therapeutics Inc., South San Francisco, United States

    Contribution

    RH, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

    Competing interests

    The author declares that no competing interests exist.

12. Bengt Hallberg

    Department of Medical Biochemistry and Cell Biology, Instititute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Contribution

    BH, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

    Competing interests

    The author declares that no competing interests exist.

13. Ruth H Palmer

    Department of Medical Biochemistry and Cell Biology, Instititute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Contribution

    RHP, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

    For correspondence

    ruth.palmer@gu.se

    Competing interests

    The author declares that no competing interests exist.

    "This ORCID iD identifies the author of this article:" 0000-0002-2735-8470

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