In the previous posting (which was originally posted over a year ago), I was able to track down some papers which uncovered evidence for the existence of various adherens junctions proteins in unicellular organisms. Well, a few days ago, I had the time to probe databases with sequence from human genes in search of homologs for adherens junction proteins in unicellular organisms.
Recall the basic components of an adherens junction as seen in the below figure:
As you can see, the cadherin is the membrane protein used to link cells together. The cadherin, in turn, is linked to the cytoskeletal microfilaments through a complex composed of beta-catenin, alpha-catenin, alpha-actinin, and vinculin.
Below is a table that lists what I found.
The human gene used to search is listed on the left, while the right hand columns list the organism that contained a match, the fraction of amino acid positions in the match that contained similar amino acids and, most importantly, the E value. The E value is a statistical measure where the rule of thumb is that E values less than 10^-4 mean the similarities between the two sequences cannot be attributed to chance. Thus, biologists infer homology if the values are less that 10^-4.
|Human protein||Human gene||Unicellular species||% positives||E value|
|Actinin, alpha 3||AAA51585.1||Monosiga brevicollis||579/894 (65%)||0|
|Actinin, alpha 3||AAA51585.1||Dictyostelium discoideum||509/868 (59%)||7.00E-163|
|Actinin, alpha 3||AAA51585.1||Polysphondylium pallidum||500/866 (58%)||9.00E-153|
|Actinin, alpha 3||AAA51585.1||Entamoeba histolytica||217/352 (62%)||1.00E-77|
|vinculin isoform VCL||AAA61283.1||Monosiga brevicollis||235/503 (47%)||6.00E-36|
|vinculin isoform VCL||AAA61283.1||Polysphondylium pallidum||205/455 (46%)||4.00E-13|
|vinculin isoform VCL||AAA61283.1||Dictyostelium discoideum||57/109 (53%)||1.00E-07|
|catenin beta-1||CAA61107.1||Volvox carteri||238/536 (45%)||1.00E-24|
|catenin beta-1||CAA61107.1||Trypanosoma brucei||90/204 (45%)||2.00E-06|
|catenin alpha-1||BAA02979.1||Monosiga brevicollis||305/756 (41%)||9.00E-2|
So what are these organisms? Below is a phylogenetic tree that shows their relationship to metazoans:
If we combine this tree with the table, we can see that alpha-actinin and viniculin homologs existed long before metazoans came onto the scene, before fungi and metazoans split.
The beta-catenin homlogs are found in green algae (Volvox), indicting that a beta-catenin-like protein may have existed in the last common ancestor of green algae/plants and animals. So far, the alpha catenins and cadherins appear to be restricted to choanflagellates and metazoans.
The bottom line here is that homologs for all components of the adherins junction existed long before the simplest of metazoans came into existence (even though no single celled organism in particular contains all components). Thus, the information was there to nudge the appearance of adherens junctions into existence when it came time for metazoans to appear.
I would also add there are many reasons to think the table listed above underestimates the extent to which these homologs are present among unicellular organisms:
1. I only used the sequence for one human gene for each of these components to search the data bases. A more wide-reaching approach would be to include sequence from various other metazoans as a probe.
2. I only searched the genomes of Monosiga, amoeboids, green algae, kinetoplastids, and Tetrahymena.
3. I used the standard BLASTP to search instead of the more sensitive PSI-BLAST.
4. We posses only a tiny fraction of all single-celled eukaryotic sequence.
Me thinks da bunny has dug up a little goldmine. In the previous essay, I shared what I uncovered about the components of adherens junctions. So let’s get up to speed about these structures. I told you they are used to connect cells together to form the sheets of cells known as epithelial tissue. Here are some more facts about these structures:
Adherens junctions provide strong mechanical attachments between adjacent cells.
• They hold cardiac muscle cells tightly together as the heart expands and contracts.
• They hold epithelial cells together.
• They seem to be responsible for contact inhibition.
• Some adherens junctions are present in narrow bands connecting adjacent cells.
• Others are present in discrete patches holding the cells together.
Adherens junctions are built from:
• cadherins — transmembrane proteins (shown in red) whose
o extracellular segments bind to each other and
o whose intracellular segments bind to
• catenins (yellow). Catenins are connected to actin filaments
Now, as I have shown, all the major components of these structures that are used to form multicellular organisms have homologs that exist in unicellular organisms. But the most interesting finding is the putative homolog for human beta-catenin in the green algae, Volvox carteri. Volvox is a actually a multicellular organism,
a fact that is going to make this rabbit hole very interesting later on.
But let’s lay out some bare information about this protein, beta-catenin. I informed you that it is a key link that connects the cytoskeleton (universal in eukaryotes) to the cadherins (membrane proteins that connect cells together). Here’s some more:
β-catenin is part of a complex of proteins that constitute adherens junctions (AJs). AJs are necessary for the creation and maintenance of epithelial cell layers by regulating cell growth and adhesion between cells. β-catenin also anchors the actin cytoskeleton and may be responsible for transmitting the contact inhibition signal that causes cells to stop dividing once the epithelial sheet is complete.
Recent evidence suggests that β-catenin plays an important role in various aspects of liver biology including liver development (both embryonic and postnatal), liver regeneration following partial hepatectomy, HGF-induced hepatomegaly, liver zonation, and pathogenesis of liver cancer.
To see how important this protein is, consider the figure below that shows the various circuitry that connects the membrane to various activity in the cell, including the expression of genes:
You can see the cadherins as the yellow lines in the two gray lines (the membrane). Connected to them are the blue circles, which represent the beta-catenins. My, they are involved everywhere. They link to the receptor tyrosine kinases (once thought to be specific to metazoans, as we have discussed). They are linked to endocytosis, the process of absorbing material into the cell. And they are linked to differentiation.
In fact, here’s a paper that outlines the importance of this protein in metazoan evolution:
Nature. 2003 Nov 27;426(6965):446-50.
An ancient role for nuclear beta-catenin in the evolution of axial polarity and germ layer segregation.
Wikramanayake AH, Hong M, Lee PN, Pang K, Byrum CA, Bince JM, Xu R, Martindale MQ.
The human oncogene beta-catenin is a bifunctional protein with critical roles in both cell adhesion and transcriptional regulation in the Wnt pathway. Wnt/beta-catenin signalling has been implicated in developmental processes as diverse as elaboration of embryonic polarity, formation of germ layers, neural patterning, spindle orientation and gap junction communication, but the ancestral function of beta-catenin remains unclear. In many animal embryos, activation of beta-catenin signalling occurs in blastomeres that mark the site of gastrulation and endomesoderm formation, raising the possibility that asymmetric activation of beta-catenin signalling specified embryonic polarity and segregated germ layers in the common ancestor of bilaterally symmetrical animals. To test whether nuclear translocation of beta-catenin is involved in axial identity and/or germ layer formation in ‘pre-bilaterians’, we examined the in vivo distribution, stability and function of beta-catenin protein in embryos of the sea anemone Nematostella vectensis (Cnidaria, Anthozoa). Here we show that N. vectensis beta-catenin is differentially stabilized along the oral-aboral axis, translocated into nuclei in cells at the site of gastrulation and used to specify entoderm, indicating an evolutionarily ancient role for this protein in early pattern formation.
Now, let’s go back to the fact that human beta-catenin appears to be homologous to an undescribed protein in Volvox. Why is this so exciting? Consider the phylogenetic tree for all eukaryotes:
If this protein is found in both green algae and metazoans, then when was the last time they shared a common ancestor? Simply trace the lineages lines to see where they meet. It looks like we can make a reasonable case that beta-catenins, used to connect cells together and to differentiate them during embryonic development, had a homolog that existed in the last common ancestor of all eukaryotes!
So let’s next nail down the homologous relationship and then watch the story become even more interesting.
Let’s take a few moments to show you that the green algae, Volvox carteri, contains sequence that apparently codes for a homolog of the human beta-catenin protein.
If you take the sequence from the human beta-catenin gene (CAA61107.1) and use it to BLAST the genome of Volvox carteri, you will retrieve “hypothetical protein VOLCADRAFT_41528 [Volvox carteri f. nagariensis]” (XP_002955847.1)
Now, human beta-catenin is 781 amino acids in length while the Volvox protein is 525 amino acids. The BLAST program is able to align the sequences such that sequence of the entire Volvox protein is matched up against human beta-catenin starting around amino acid position 150. When this is done, 144/536 (27%) of the positions are identical and 238/536 (45%) positions contain amino acids that have similar properties. Given the phylogentic distance between these two species, that is pretty impressive. Could it be simple coincidence that these positions match up like this? No. The E value associated with this match is 1e-25. The BLAST program is designed such that matches with E values less that 1e-04 are not attributed to chance. This is why biologists infer homology when the E value is that small. And given that 1e-25 is smaller than 1e-04 by several orders of magnitude, we can safely assume these two sequences are homologous.
But it actually gets better than this.
Proteins are modular structures composed of domains, which are relatively short spans of amino acids typically associated with a function. Beta-catenin is composed of a series of such spans known as armadillo (Arm) repeats located in the middle bulk of the protein. The Arm is approximately 40 amino acids in length and consists of three alpha-helices where the second and third alpha helix pack against each other. In fact,
The 3-dimensional fold of an armadillo repeat is known from the crystal structure of beta-catenin, where the 12 repeats form a superhelix of alpha helices with three helices per unit (PUBMED:9298899). The cylindrical structure features a positively charged grove, which presumably interacts with the acidic surfaces of the known interaction partners of beta-catenin.
The bottom line is that beta-catenin contains 12 Arm repeats in series such that the protein has the overall shape of a super-helix (reminiscent of DNA structure) as can be seen in the bottom figure below:
We’ll come back to this structure in the next posting. For now, another way to visualize this is using NCBI’s Conserved Domain Database (CDD), which is “a collection of sequence alignments and profiles representing protein domains conserved in molecular evolution. It also includes alignments of the domains to known 3-dimensional protein structures in the MMDB database.”
Below is the CDD representation of beta-catenin:
You can see the “12 repeats form a superhelix of alpha helices with three helices per unit” represented as four blocks labeled in red as ARM (the first block is more Arm-like, probably because of sequence divergence). I’m guessing that the little mountain-triangles under the number line (that represents the amino acids) correspond to the actual Arm repeats, as there are 12 sets (3 per box/unit).
Pay attention to this pattern. Why? Let’s now consider the CDD representation of the homolog from Volvox:
My goodness, they look almost the same! Like beta-catenin, the Volvox protein is a series of Arm repeats. Instead of twelve, there appear to be ten, but they seem to be broken into four units that are laid out almost identically to the human beta-catenin, even to the point of there being an overlap between units 3 and 4.
So we are on pretty solid ground when inferring the human and green algae proteins are homologous:
1. The entire length of the Volvox protein aligns with human beta catenin with an E-value of 1e-25.
2. Both proteins are a series of Arm repeats that show a very similar CDD representation, indicating that these proteins have similar structures.
Let’s now have some fun.
Now that we have seen that VOLCADRAFT_41528 (from Volvox carteri ) is likely to be homologous to human beta catenin, it becomes reasonable to propose that something very similar to beta-catenin existed in the last common ancestor of all eukaryotes.
However, if we are going to make this rather radical claim, it would help if we could find homologs in other lineages. So let me begin by pointing out that homologs of human beta catenin exist in all three basal metazoan lineages: Trichoplax, sponges, and comb jellies. Among metazoans, the beta catenin sequence is strongly conserved. For example, 340/592 (58%) of the positions have identical amino acids when sponge sequence is aligned with human sequence.
So beta-catenins are universally present among metazoans and its homolog may exist in multicellular algae, Volvox. But what about true unicellular organisms?
If you go back to the table I posted a few days ago, we do have one such example – Trypanosoma brucei, a protozoan that causes African sleeping sickness, has a protein that has similar amino acids in 90/204 (45%) positions. But the E value for this match is only 2.00E-06. Smaller than 1e-04, but not that much. The bunnah wants more crunch in his carrot.
To better resolve this issue, I simply took the next logical step – I used the Volvox homolog to BLAST other green algae and various protozoan lineages. The results are shown in the below table:
|Unicellular species||% identity||% positives||E value||# Arm repeats||Tree color|
|Chlorella variabilis||177/546 (33%)||257/546 (48%)||5.00E-36||10||Green|
|Micromonas sp. RCC299||120/394 (31%)||185/394 (47%)||9.00E-29||9||Green|
|Polysphondylium pallidum||101/317 (32%)||156/317 (50%)||6.00E-22||8||Purple|
|Chlamydomonas reinhardtii||122/406 (31%)||190/406 (47%)||1.00E-20||7||Green|
|Theileria parva||98/373 (27%)||172/373 (47%)||1.00E-19||9||Pink|
|Ostreococcus lucimarinus||92/296 (32%)||138/296 (47%)||2.00E-19||5||Green|
|Dictyostelium discoideum||93/303 (31%)||151/303 (50%)||3.00E-20||8||Purple|
|Perkinsus marinus||113/367 (31%)||165/367 (45%)||4.00E-18||9||Pink|
|Monosiga brevicollis||100/327 (31%)||152/327 (47%)||2.00E-17||6||Purple|
|Paramecium tetraurelia||79/310 (26%)||136/310 (44%)||7.00E-12||8||Pink|
|Tetrahymena thermophila||76/285 (27%)||121/285 (43%)||1.00E-10||9||Pink|
|Trypanosoma brucei gambiense||134/520 (26%)||228/520 (44%)||1.00E-26||5||Yellow|
|Leishmania major||140/538 (27%)||227/538 (43%)||3.00E-17||5||Yellow|
As you can see, there are many homologs of the Volvox protein that was, in turn, homologous to metazoan beta-catenin. And most of them appear to have 8 or more Arm repeats. Also, in case you are not familiar with all those species, the column on the far right indicates the colored region of the phylogenetic tree from the figure below:
As you can see, 4/5 major clades are represented, vastly strengthening the case that a beta-catenin-like protein was present in the last common ancestor of all eukaryotes.
Anyway, most of those matches are listed as hypothetical proteins. In the next posting, we’ll talk about one that is not.
One of the organisms that has a homlog to the Volvox version of beta-catenin is Dictylostium, otherwise known as a slime mold. This organism normally exists as single-celled amoeba, but when stressed, the cells seek each other out to form a multicellular state that looks like a slug, where all cells coordinate with each other for motility and reproductive purposes.
Below is a figure of the lifecycle of this organism:
As you can see, this organism can exist in an amoeboid state, a flagellated state, a multicellular state that mimics slugs and fungi, and as a spore. It even undergoes meiosis. All that biotic diversity packed into a single genome.
Here is a nice video that allows you to see this creature in action:
As mentioned before, the homologs to the Volvox version of beta-catenin are mostly annotated as hypothetical proteins because they were identified from DNA sequence rather than biochemical or genetic screens. Not so with Dictylostium. Its homolog is known. And has been studied. It’s called aardvark.
Remember that beta-catenins had a dual function. Not only did they play a crucial role in connecting a membrane protein to the cytoskeleton to form the adherens junctions used to connect cells, they also could travel to the nucleus to activate genes involved in growth and development. Well, feast your eyes on the function of aardvark:
Nature 408, 727-731 (7 December 2000)
Mark J. Grimson1,2, Juliet C. Coates2,3,4, Jonathan P. Reynolds3, Mark Shipman3, Richard L. Blanton1 & Adrian J. Harwood3
Adherens junctions and beta-catenin-mediated cell signalling in a non-metazoan organism
Mechanical forces between cells have a principal role in the organization of animal tissues. Adherens junctions are an important component of these tissues, connecting cells through their actin cytoskeleton and allowing the assembly of tensile structures1, 2, 3, 4. At least one adherens junction protein, beta-catenin, also acts as a signalling molecule, directly regulating gene expression5, 6, 7. To date, adherens junctions have only been detected in metazoa, and therefore we looked for them outside the animal kingdom to examine their evolutionary origins. The non-metazoan Dictyostelium discoideum forms a multicellular, differentiated structure8. Here we describe the discovery of actin-associated intercellular junctions in Dictyostelium. We have isolated a gene encoding a beta-catenin homologue, aardvark, which is a component of the junctional complex, and, independently, is required for cell signalling. Our discovery of adherens junctions outside the animal kingdom shows that the dual role of beta-catenin in cell–cell adhesion and cell signalling evolved before the origins of metazoa.
So what do we have here? Beta-catenin is a protein with two different crucial roles to play in metazoan existence: it is a key component of the adherens junction, thus epithelial tissue, and it is part of a key circuit that regulates gene expression needed for growth and development. In essence, beta-catenin integrates information from multiple sources: the genome, the cytoskeleton, the membrane, and the environment.
As you can now see, this integrator existed prior to the existence of metazoan life, where it plays same basic functions in an organism that exists most of the time in a single-celled state. What’s more, the integrator apparently has homologs in many distantly related eukaryotes, strongly suggesting it was part of the first truly eukaryotic cells. In other words, from the beginning of eukaryotic life, an important component of multicellular existence was already in existence.
So where did beta-catenin come from? Let’s look at that next.
[Added: Aardvark also works to support the Volvox sequence is a beta-catenin homolog: human beta-catenin sequence is more similar to Volvox sequence than Dictylostium sequence, yet the latter is an accepted homolog of human beta-catenin].
I have previously tried to show you that it is quite plausible to propose that a protein essential in two multicellular processes existed in the last common ancestor of all eukaryotes. Thus, this could be one front-loaded feature to these cells that would, sooner or later, help to nudge animal life into existence. But if it is too difficult to believe that something like beta-catenin is as old as the eukaryotic cell itself, let me make it even more clear that beta-catenin was always in the cards. How? By showing you that even if beta-catenin is not quite as ancient as I propose, its very existence was front-loaded by the existence of a remarkably similar homolog – alpha importins.
What are alpha importins? First, you need to step back a moment and reconsider the design of the eukaryotic cell – the nucleus, which contains the genetic material (genotype) is separated from the ribosomes which ultimately express the genetic material (phenotype) by a membrane. So, when it comes to the various proteins that interact with the DNA, they are first synthesized by the ribosomes out in the cytoplasm and then they must be shuttled into the nucleus. The alpha importins come into play when it comes to shuttling proteins into the nucleus. Their job is to recognize signals on newly made proteins that act as passwords for access into the nucleus. Once the alpha importins find the signal (known as the nuclear localization signal (NLS)) on some cargo protein that is supposed to be in the nucleus, they bind to it and then interact with another protein known as beta importin. Together, the complex of alpha importin + beta importin + cargo enter the nucleus through the nuclear pore complex. Here’s a figure to help you visualize it:
Given that alpha importins play a basic and crucial role in the eukaryotic cell by allowing proteins entry into the nucleus, it is quite reasonable to proposed that alpha importins are as old as the eukaryotic cell itself. And as far as I have been able to determine, they are universal among eukaryotes. Also, their sequence is highly conserved. For example, when alpha importin from rats is compared to those from the green algae Chlamydomonas reinhardtii, 259/540 (48%) positions contain the same amino acid and 351/540 (65%) positions contain amino acids with the same or similar properties.
So why think alpha importins and beta catenins are related? For starters, go back to my table of beta catenin homologs in unicellular, eukaryotic organisms. As we saw, by using the Volvox version of beta catenin to probe data bases, I retrieved lots of hypothetical proteins and a known beta catenin homolog– aardvark. But the homologs from Theileria parva, Perkinsus marinus, and Leishmania major were all alpha importins. If we accept the Volvox protein as a beta catenin, then we have homologs from three different protozoa with E values ranging from 3.00E-17 to 1.00E-19.
What’s even more striking is the fact that both alpha importins and beta catenins are composed of a series of nine or so Arm repeats arranged in a similar many. Consider the CDD representation of the Arm domains from the rat alpha importin:
Notice the pattern of nine Arm repeats broken into three sets with the second and third set overlapping. The domain attached to the front end is IBB and it is the region that sticks to the beta importin.
Now, consider what a rice alpha importin looks like:
Or alpha importin from fruit flies:
Or the green algae, Chlamydomonas:
How about one of our homologs mentioned above, the protozoan Perkinsus marinus:
Or another homolog from Theileria parva:
Or the protozoan Leishmania major:
Starting to notice a pattern among vertebrates, invertebrates, plants, algae, and protozoa alpha importins?
So what is the domain organization of human beta catenin again? Oh yeah, here it is:
Let’s make an even stronger case in the next essay.
In the last entry, we saw that beta catenins and alpha importins appear to have a strikingly similar domain organization as seen by the CDD representations. So what do the two proteins actually look like?
And here’s alpha importin:
First, a review.
We’re looking at two different eukaryotic proteins: beta catenin and alpha importin. Beta catenin plays two different crucial roles in metazoan life: 1) It is a key component of the adherens junction which connects cells together and 2) it is involved in the transcription of genes that play an important role in the development of the embryo and the maintenance of organs. This is a neat example of one protein playing two important roles in metazoan life. A simplified figure is shown below, where the beta catenin is represented by the pink circle:
Next are the alpha importins. They transport proteins into the nucleus through the nuclear pore complex. The figure below shows the basic mechanism involved:
The alpha importin is shown in blue. It recognizes and binds the nuclear localization signal (NLS) on a protein that is destined for the nucleus (in the above figure, it is the experimentally designed radioactive protein) and then binds with another protein, beta importin, to be transported into the nucleus.
It is my hypothesis that the alpha importins imposed a form of guidance to evolution by front-loading the eventual emergence of the beta catenins which would, in turn, facilitate the evolution of metazoa. The first line of support for this hypothesis would be to show a homologous relationship between these two different proteins (and as far as I have been able to tell, no one has seriously proposed this). So allow me to make that case.
I began to suspect a homologous relationship between the alpha importins and beta catenin from sequence comparison between a Volvox protein that I previous scored as a beta catenin-like protein and human beta catenin. Put simply, when I probed various protozoan genomes with the Volvox sequence, I found three matches that turned out to be alpha importins.
So I decided to BLAST human alpha importin sequence against human beta catenin sequence. The two proteins share 96/421 (22%) positions with the same amino acid, 170/421 (40%) positions with a biochemically similar amino acid, with an E value of 2e-11 (recall that E values less than 1e-4 are considered homologous).
Added to these sequence data is the fact that the alpha importins and beta catenins have a strikingly similar structure.
Now let’s make it even more interesting by considering the functional overlaps between the two proteins:
1. Both proteins proteins have the ability to transport across the nuclear pore complex.
2. Both proteins have the ability to bind to multiple partners. Alpha importins can bind to any protein that contains a NLS and beta catenins bind to over 20 different proteins.
3. It gets much more interesting. While beta catenin transports into the nucleus, it doesn’t have a NLS signal and enters without the help of alpha importin:
Beta-catenin is imported into the nucleus by binding directly to the nuclear pore machinery, similar to importin-beta/beta-karyopherin or other importin-beta-like import factors, such as transportin. These findings provide an explanation for how beta-catenin localizes to the nucleus without an NLS and independently of its interaction with TCF/LEF-1. This is a new and unusual mechanism for the nuclear import of a signal transduction protein. – Fagotto F, Glück U, Gumbiner BM. 1998. Nuclear localization signal-independent and importin/karyopherin-independent nuclear import of beta-catenin. Curr Biol. 8(4):181-90.
4. Like beta catenin, alpha importins can pass through the nuclear pore complex without assistance (in other words, the beta importin partner is not needed):
These results indicate that importin alpha alone can enter the nucleus via a novel pathway in an importin beta- and Ran-independent manner. Furthermore, this process is evolutionarily conserved as similar results were obtained in Saccharomyces cerevisiae. – Miyamoto Y, Hieda M, Harreman MT, Fukumoto M, Saiwaki T, Hodel AE, Corbett AH, Yoneda Y. 2002. Importin alpha can migrate into the nucleus in an importin beta- and Ran-independent manner. EMBO J. 21(21):5833-42.
5. Best of all is the fact that beta catenins can function as an importin!
Nuclear accumulation of beta-catenin plays an important role in the Wnt signaling pathway. In the nucleus, beta-catenin acts as a transcriptional co-activator for TCF/LEF family of transcription factors. It has been shown that lef-1 contains a typical basic type nuclear localization signal (NLS) and is transported into the nucleus by the conventional import pathway. In this study, we found that a mutant lef-1 lacking the classical NLS accumulated in the nucleus of living cells, when beta-catenin was co-expressed. In addition, in a cell-free import assay, lef-1 migrated into the nucleus in the presence of beta-catenin alone without any other soluble factors. In contrast, another mutant lef-1 lacking the beta-catenin binding domain failed to migrate into the nucleus, even in the presence of beta-catenin. These findings indicate that beta-catenin alone can mediate the nuclear import of lef-1 through the direct binding. Collectively, we propose that there are two distinct pathways for the nuclear import of lef-1: importin alpha/beta-mediated and beta-catenin-mediated one, which provides a novel paradigm for Wnt signaling pathway. – Asally M, Yoneda Y. 2005. Beta-catenin can act as a nuclear import receptor for its partner transcription factor, lymphocyte enhancer factor-1 (lef-1). Exp Cell Res. 308(2):357-63.
So when it comes to the transcription factor lef-1, beta catenin can substitute for alpha importin.
Considering all the structural, sequence, and functional similarities, I think we’re on pretty solid ground in proposing a homologous relationship between the alpha importins and beta catenins. And given that alpha importins are essentially universal among eukaryotes, playing the key eukaryotic role of transporting proteins into the nucleus, it is likely that the alpha importins functioned to nudge the beta catenins into existence. In other words, we can view this core aspect of the eukaryotic cell design as a preadaptation for multicellularity, as if the eukaryotic cell was meant to facilitate the emergence of complex, multicellular existence.